Gallbladder Cancer

Abstract

Gallbladder carcinoma is a form of cancer that develops in the gallbladder, an organ located beneath the liver. This condition poses a clinical challenge due to its late diagnosis and aggressive tumor behavior. Risk factors include the presence of gallstones, advanced age, and obesity. Diagnosis of gallbladder carcinoma requires the use of various diagnostic techniques such as ultrasound, computed tomography, and magnetic resonance imaging. Cholecystectomy, the surgical removal of the gallbladder, is the primary treatment for gallbladder carcinoma. However, management and treatment may require a multidisciplinary approach, which can also involve chemotherapy, radiation therapy, and targeted therapies. Increased awareness of this disease is necessary to improve early diagnosis and treatment options, ultimately enhancing survival rates and improving the quality of life for patients with gallbladder carcinoma.

1. Introduction

Gallbladder cancer is a rare and highly aggressive malignancy that presents significant challenges for diagnosis and treatment [1]. Although it is a relatively uncommon cancer, its poor prognosis and the lack of effective treatments make it a significant concern for patients and healthcare providers alike [2]. Gallbladder cancer is often asymptomatic in its early stages, making it difficult to detect and diagnose [3]. Additionally, there are several risk factors associated with gallbladder cancer, including gallstones, chronic inflammation, obesity, and genetic factors, which further complicate the diagnostic process [1].

Treatment of gallbladder cancer typically involves surgery, but the extent of resection depends on the stage of the tumor [2]. Adjuvant therapies such as chemotherapy and radiation therapy have limited efficacy in the treatment of gallbladder cancer, but they may be used in select cases [3]. In this chapter, we will discuss the anatomy, pathogenesis, diagnosis, and treatment of gallbladder cancer, as well as its prognosis and follow-up care.

2. Anatomy

The gallbladder is a pear-shaped organ located on the underside of the liver in the right upper quadrant of the abdomen. It measures approximately 7–10 cm in length and 3–5 cm in diameter when fully distended [1]. The wall is thin with a thickness of 2–3 mm, and the mucosa has a simple columnar epithelium. Underneath, without a true submucosa, a single smooth muscle layer with longitudinal, circular, and oblique arrangement of fibers is observed.

The gallbladder is divided into three parts: the fundus, the body, and the neck (Figure 1). The fundus is the most distal portion of the gallbladder and projects beyond the inferior margin of the liver. The body of the gallbladder is in the midportion of the organ, while the neck is the narrowest portion of the gallbladder, which connects it to the cystic duct [4].

Figure 1.

Gallbladder anatomy.

The gallbladder is supplied by the cystic artery, which is a branch of the right hepatic artery. The cystic vein drains into the portal vein. The gallbladder is innervated by the cystic nerve, which is a branch of the hepatic plexus. The cystic duct is the narrow tube that connects the gallbladder to the common bile duct, which carries bile from the liver to the small intestine [5].

The gallbladder functions as a storage and concentration reservoir for bile, a fluid produced by the liver that aids in the digestion and absorption of fats. When food enters the small intestine, the gallbladder contracts and releases stored bile into the duodenum via the common bile duct. The presence of gallstones, inflammation, or tumors in the gallbladder can disrupt this normal process and lead to various pathologies, including gallbladder cancer [1].

3. Pathophysiology and risk factors

For a long time, Cholangiocarcinoma (CC) has been regarded as an appropriate model for illustrating the relationship between chronic inflammation and cancer. In 1920, Archibald Leitch chose to study CC due to its association with a “…particular endogenous irritant,” gallstones. He implanted human gallstones, pebbles, and tar pellets into the gallbladders of guinea pigs and observed a progressive worsening, starting from epithelial desquamation to lesions, and in some cases, the emergence of invasive adenocarcinomas [4]. He repeated the same experiment using melted lanolin, a soft material capable of causing repeated damage to cells, which did not, however, induce any macroscopic changes in the gallbladder. Leitch concluded that the damage was caused not by the nature of the irritant but by the mere presence of a foreign body, which was responsible for the development of a “[...] pathological state of the tissues” predisposing to the onset of cancer [6], the individual risk factors for gallbladder carcinoma:

• Ethnicity: It plays a colossal role in both the prevalence of gallbladder disease and the composition of gallstones. Cholesterol stones prevail in the Western world, while pigment stones are more common in Asia. Gallbladder cancer is rare in industrialized countries. In the United States, it accounts for 0.5% of gastrointestinal malignancies, with fewer than 5000 cases per year (1–2.5 cases per 100,000) [5]. Worldwide, gallbladder carcinoma has a low incidence, less than 2 cases per 100,000, although there is considerable variability. High incidence rates are found in Native Americans of North and South America, resulting in unusually high mortality rates, particularly among women. For example, in La Paz (Bolivia), the incidence is 15.5 per 100,000 in women (compared to 7.5 per 100,000 in men), and in New Mexico, it is 11.3 per 100,000 in women (compared to 4 per 100,000 in men). Furthermore, gallbladder carcinoma is one of the leading causes of cancer-related death in the female population of Chile, surpassing even breast, lung, and cervical cancer. In fact, it has been observed that in certain populations in North America (Native Americans of Western America and New Mexico), the incidence of gallbladder cancer is statistically higher (the annual incidence of gallbladder carcinoma per 100,000 individuals with gallstones is 74.9% in females of this race, with a range from 65.3 to 87.7%). Other regions at high risk include Eastern Europe (14 per 100,000 in Poland), northern India (21.5 per 100,000 in Delhi), and South Pakistan (11.3 per 100,000). An intermediate incidence risk (ranging from 3.7 to 9.1 per 100,000) is observed in Latin American populations, Israel (5 per 100,000), and Japan (7 per 100,000), related to the frequent congenital anatomical abnormalities associated with this cancer that are found in the Japanese population. Finally, areas where the frequency is increasing in recent years include Shanghai and China. These data also reflect the prevalence of cholelithiasis or Salmonella infections, which are highly prevalent in Indian populations in America.

• Gender: Gallbladder cancer exhibits a pronounced predilection for the female gender, especially in high-risk regions where the incidence among women reaches such remarkable heights that it warrants the appellation of “female gender bias.” Females, particularly during the reproductive age, are twice as likely to develop gallstones. It is known that estrogens (endogenous or pharmacologically administered) increase the secretion of cholesterol into the bile. On the other hand, progesterone decreases the gallbladder’s emptying capacity, promoting stasis [1].

• Age: The risk of developing gallbladder cancer escalates concomitantly with advancing age, with the highest morbidity rates observed within the age range of 50–60 years (encompassing 80–90% of all gallbladder carcinoma cases). This compelling data holds immense significance when juxtaposed with the equally noteworthy prevalence of gallstone disease in women, which manifests approximately a decade earlier within a relatively younger age cohort [3]. The type of stones also varies depending on the age group: younger patients mostly have cholesterol stones (due to bile oversaturation), while older individuals have a higher incidence of pigment stones. Additionally, age is a factor that increases the risk of complications, emphasizing the crucial role of preventive cholecystectomy.

• Chronic inflammation: Intriguing studies reveal that approximately 25% of cases manifest a fascinating phenomenon known as the porcelain gallbladder, although recent research endeavors have cast doubt upon this observation. Remarkably, it seems that only gallbladders showcasing partial calcifications or multiple punctate calcifications precisely nestled within the glandular expanse of the mucosa are to be considered as true premalignant conditions, warranting proactive removal as a preventive measure. In addition, the persistent presence of chronic bacterial infections fervently fuels gallbladder irritation and inflammation, adding another layer of complexity to the intricate puzzle. Notably, carriers of the notorious S. Typhi bacterium face an astonishingly heightened risk, spanning an alarming 8 to 12-fold increase of eventually succumbing to the treacherous grips of carcinoma [4]. Meanwhile, the cunning culprit H. pylori emerges as an insidious player, with an odds ratio of 6.5 in the Japanese population and an equally compelling ratio of 5.86 in their Thai counterparts, perpetuating the bewildering web of gallbladder cancer causation. Furthermore, the intriguing realm of primary sclerosing cholangitis (PSC) unfurls an intriguing association, with a staggering 37% of cases exhibiting coexisting dysplasia while 14% plunge into the abyss of adenocarcinoma.

• Congenital anomalies of the biliary tract: Unveiling their prominence predominantly within the Asian populace, these captivating aberrations encompass the enigmatic domain of pancreaticobiliary junctional irregularities. Within this captivating tapestry, the prophylactic act of cholecystectomy assumes paramount significance, acting as a robust shield against the looming specter of gallbladder cancer that hauntingly pervades the afflicted individuals with exceptional frequency [5].

• Gallbladder polyps: Within the enigmatic realm of the gallbladder, a captivating subplot emerges—polyps. These elusive entities captivate our attention, affecting 5% of adults, often masquerading as potential harbingers of gallbladder malignancy. However, amidst this intricate tapestry, most gallbladder polyps gracefully assume the role of benign cholesterol lesions or fibromyoglandular growths, devoid of malicious intent. Yet, lurking within this benign facade, true papillary neoplasms (formerly known as adenomas) may conceal their treacherous potential, their virulence intricately linked to their voluminous presence and flourishing vascularity. As we delve deeper into this captivating narrative, a remarkable revelation surfaces—polyps with a diameter less than 1cm seldom harbor sinister aspirations, assuring a semblance of respite. However, as the stage expands, embracing polyps exceeding the 2 cm threshold, a tantalizing secret reveals itself, their bosom potentially concealing malignant neoplasms. Thus, a symphony of data illuminates our path, emphasizing a heightened incidence of cancer in polyps boasting a diameter surpassing the majestic 1 cm mark and those adorned with a delicate vascular pedicle [7, 8]

• Gallbladder stones: Unveiling the intricate interplay between gallbladder cancer and its stony companions, the enigmatic saga of cholelithiasis unfolds. A compelling tale emerges as a positive history of gallstone affliction casts a shadow of elevated risk, with a resolute relative risk of 4.9. It is a realm where dualities coexist, where the majority (ranging from 69 to 100%) of gallbladder cancer warriors share a clandestine bond with gallstones, though not every warrior bears this emblem. Yet, within the fabric of this entwined narrative, a symphony of coexistence resonates, whispering of gallstones assuming the enigmatic role of co-factors, propelling the genesis of gallbladder carcinoma. A poignant revelation surfaces, shining a radiant light upon Native Americans, adorned with an abundance of cholesterol stones, who, in their unique tapestry, bear witness to an amplified incidence of gallbladder cancer [7]. As we traverse this intricate labyrinth, dimensions assume significance—size expands beyond mere physicality, transcending the 3 cm threshold, accompanied by an army of brethren, numbers and weight, their presence inextricably linked to an escalated risk of cancer. Yet, amidst this grand stage, the passage of time assumes a lesser role, its duration holding a diminished sway. Within the realm of gallstone- laden warriors battling cancer, a dichotomy of stone composition unfolds—cholesterol stones proudly claim their dominion, while pigment stones grace the stage with a more subdued presence. Inextricably intertwined, the veil of cancer incidence lifts, exposing the profound impact of cholecystectomies, their dwindling numbers invoking a crescendo of carcinogenic potential. Beyond the realm of cholesterol, the shadows of bile’s carcinogenicity come to light—bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, and lithocholic acid), whether tethered to conjugates or roaming free, dance amidst the population mosaic, unveiling their disparate distribution. Within the realm of gallstone warriors, striding alongside their cancerous comrades, a revelation emerges—an ethereal surge of deconjugated lithocholic acid, reaching crescendos of tumorigenicity, weaving the intricate threads of endogenous carcinogenesis within the gallbladder’s realm. As we delve deeper into this captivating narrative, an array of factors intertwined with gallstone formation springs forth, further illuminating the complex tapestry that weaves the tale of gallbladder affliction [8, 9]

• Family history and genetics: Genetic susceptibility is a key factor in stone formation, which is a stepwise process regulated by numerous genes. Among the better-known genes are apolipoprotein E (APOE) and B (APOB), cholesterol ester transfer protein (CEPT), cholesterol 7-alpha-hydroxylase, cholecystokinin A receptor (CCAR), and LDL receptor (LDLR). The spotlight shines brightly on the apolipoprotein B (APOB) gene, standing alone as the unequivocally identified culprit in gallbladder carcinogenesis [9].

  The gene most recently associated with stone formation and predisposition to gallbladder cancer is ABCG8, which encodes a cholesterol transporter present on the canalicular membrane of hepatocytes. However, it is important to note that cholelithiasis is a polygenic disease with a complex etiology.

• Obesity and metabolic syndrome/dyslipidemia/diabetes mellitus: Obesity, especially central (visceral) obesity, is a well-known risk factor for gallbladder disease. One in four obese individuals suffers from gallstones. Individuals with dyslipidemia (low levels of HDL, high levels of triglycerides) also have an increased risk of stone formation. These two conditions (central obesity and dyslipidemia), along with fasting hyperglycemia and hypertension, are part of Metabolic Syndrome. One of the most plausible mechanisms involves the enhancing role of high insulin levels (resulting from insulin resistance) on cholesterol transporters in hepatocytes.

• Rapid weight loss: A hypocaloric diet leading to a weight loss of more than 1kg per week significantly increases the risk of gallstone formation. This condition is frequently observed during the first 6 weeks of follow-up in severely obese individuals undergoing bariatric surgery.

• Total parenteral nutrition (TPN): TPN is a well-known risk factor for the formation of sludge or biliary sludge. After approximately 5–10 days of intensive TPN therapy, sludge formation is common, reaching a prevalence of 50% if TPN is extended to 30 days and 100% for therapies lasting more than 6 weeks. This condition occurs due to the cessation of enteric stimulation on the gallbladder and the resulting biliary stasis.

• Other associated conditions: Pathologies associated with the development of gallstones include cirrhosis, hepatitis C, non-alcoholic fatty liver disease, sickle cell anemia, Crohn’s disease, and cystic fibrosis. In the latter two conditions, malabsorption leads to depletion of total bile salts and indirect cholesterol supersaturation in the bile.

• Other lifestyle factors: Other risk factors include cigarette smoking and alcohol consumption (in men only) [8].

From a genetic perspective, the polymorphism of the ABCG8-DH19 partner gene, ABCG5/G8, was the first discovered genetic risk factor for the formation of cholesterol gallstones [10]. This lithogenic polymorphism leads to a gain of function in the protein, allowing for increased biliary secretion of cholesterol on the canalicular side of hepatocyte membrane, contributing to bile supersaturation and promoting stone formation [11]. Interestingly, in addition to its role as a risk factor for gallstone formation, this polymorphism has also been associated with an increased risk of developing gallbladder cancer in different ethnicities [12, 13].

Furthermore, polymorphisms of genes related to the immune system, inflammation, and oxidative stress have been associated with an increased risk of gallbladder cancer. These genes include PTGS2 [14], TLR2, TLR4 [15], IL1RN, IL1B [16], IL10 [17], IL8 [18], CCR5 [19], LXRβ [20], and OGG1 [21].

Studies in murine models have shown that mice with cholesterol microstones (early stage of gallstone formation) exhibited a gallbladder characterized by increased mucosal layer thickness and elevated interleukin-1 and myeloperoxidase activity in the gallbladder wall [22]. Morphological changes (epithelial hyperplasia, hypertrophic muscularis propria, and increased wall thickness) were observed as early as four weeks. These changes were accompanied by an inflammatory infiltrate composed of eosinophils, macrophages, neutrophils, and lymphocytes within the lamina propria [23]. At this point, Maurer et al. demonstrated that T lymphocytes are crucial for the development of cholesterol gallstones, as Rag2 -/- mice lacking T and B lymphocytes were resistant to cholesterol gallstone formation despite being fed a lithogenic diet for 8 weeks [24]. This showed that, at least in murine models of cholelithiasis, chronic inflammation of the gallbladder occurs in the early stages of lithogenesis as a local response to the presence of cholesterol supersaturation in bile even before the formation of macroscopic gallstones [25].

Gallstones, along with the associated cholecystitis, lead to a sequence of events that result in dysplasia and eventually carcinoma of the gallbladder in over 90% of cases. This assertion is supported by the fact that 83% of gallbladders with stones are associated with inflammation, showing at least one focus of hyperplasia, while 13.5% exhibit atypical hyperplasia and 3.5% show carcinoma in situ.

Two patterns of malignant transformation have been observed in the gallbladder: the metaplasia- dysplasia-carcinoma sequence (Figure 2) and the adenoma-carcinoma sequence. However, carcinogenesis related to biliary lithiasis primarily occurs through the metaplasia-dysplasia- carcinoma pathway, rather than transformation from a pre-existing benign tumor lesion.

Figure 2.

Progression of gallbladder cancer.

Metaplasia is a common finding in gallbladder tissues exposed to gallstones, with frequencies ranging from 59.5 to 95.0% for pseudopyloric metaplasia and 9.5–58.1% for intestinal metaplasia [26, 27]. Furthermore, the severity of lesions found in the epithelium worsens with increasing weight, volume (particularly if it is > 3 cm), and variation in the shape of gallstones (spherical shape being less injurious) [28].

Moreover, metaplastic lesions arise under the expression of key transcription factors that redirect the epithelial phenotype to a different type. In fact, gallbladder metaplasia is often associated with the expression of CDX2 [29], a homeobox transcription factor involved in the normal development of the intestine, commonly found in intestinal metaplasia of the esophagus and stomach as well [30]. The normal epithelium of the gallbladder does not express CDX2, and the surrounding leukocytes mainly consist of T lymphocytes (CD3+, CD4+, and CD8+) and populations of macrophages (CD14+, CD68+, and CD163+), with low or absent levels of B cells (CD20+). In contrast, the CDX2-positive metaplastic epithelium of the gallbladder is often infiltrated by dense populations of T cells, B cells, and macrophages.

Furthermore, the presence of metaplastic changes is correlated with an increase in the average thickness of the gallbladder wall. Diffuse thickening of the gallbladder wall, defined as an enlargement exceeding 3 mm measured on ultrasound examination, can be observed in primary inflammatory processes, such as acute, chronic, and acalculous cholecystitis.

Certain types of infections, likely due to bile and bile salt deconjugation, can also contribute to the development of gallbladder cancer (infection by Salmonella typhi, Clonorchis sinensis, Opisthorchis viverrini, as well as various species of Escherichia, Klebsiella, and Helicobacter) [31]. Although little is known about the true carcinogenic effect of Salmonella in the absence of gallstones, there is consistent epidemiological evidence that chronic Salmonella infection is a risk factor for gallbladder cancer. It is known that Salmonella infection is even more potent in this regard when gallstones are present. Both gallstones and bacteria can induce an inflammatory response, so it is plausible to hypothesize that the combination of these agents increases the risk of developing gallbladder cancer.

Reflux of pancreatic juice into the bile ducts and the gallbladder itself can underlie the development of gallbladder carcinoma, as supported by experimental findings that have shown a higher incidence of this disease in individuals with anomalous drainage of the Wirsung and common bile duct into the duodenum (Anomalous arrangement of the pancreaticobiliary duct AAPBD) [32]. These patients exhibited an extramural common segment of the two ducts, i.e., an extrasphincteric portion (evaluated by cholangiography), which allowed reflux of pancreatic juice into the bile duct. AAPBD is a congenital biliary anomaly associated with a high frequency of gallbladder carcinoma, with relative risks ranging from 167.2 to 419.6 times higher in AAPBD patients compared to the general population [33]. In these patients, carcinogenesis progresses through a sequence of metaplasia- dysplasia-carcinoma driven by chronic inflammation, like gallbladder cancer caused by gallstones. Under the influence of this chronic inflammation, activation of pancreatic enzymes, changes in the bile acid fraction, and production of mutagenic or occasionally carcinogenic substances may occur [34]. It is interesting to note that the prevalence of KRAS mutations is higher in AAPBD-related gallbladder cancer compared to non-related cases [35, 36], making it more etiologically like pancreatic cancer (which has a high prevalence of KRAS mutations) than LB-associated gallbladder cancer (where the frequency of such rearrangement is low or nonexistent). Generally, cancer associated with anomalous pancreaticobiliary ductal junction (APBDJ) occurs at a young age and is less correlated with female gender and cholelithiasis.

Some diseases are commonly associated with the development of gallbladder cancer è [37]. One of these is “porcelain” gallbladder, although recent studies do not support this correlation, although they still recommend gallbladder removal due to the associated symptoms, which are also difficult to diagnose preoperatively [38]. Adenomatous polyps have always been associated with a high risk of cancer when they exceed 10 mm in size, but neoplastic polyps can also be smaller, so careful long- term follow-up is necessary to avoid setting a criterion that is too permissive. Malignancy characteristics of polyps are determined by their irregular and heterogeneous echotexture, generally isoechoic with the liver, or hypoechoic, as well as by thickening of the gallbladder walls. In general, 3–8% of polyps are malignant, regardless of size (0–5% if <10 mm) [39]. Furthermore, certain autoimmune diseases have been associated with an increased risk of tumors [40], including gallbladder cancer [41]. Recently, six autoimmune conditions have been correlated with higher standardized incidence rates for gallbladder cancer: primary sclerosing cholangitis (PSC), celiac disease, Crohn’s disease, pernicious anemia, ulcerative colitis, and polymyositis/dermatomyositis. PSC is the classic hepatobiliary manifestation of inflammatory bowel diseases and other immunomediated diseases, characterized by bile duct destruction and progression to end-stage liver disease. Chronic lesions occur in small, medium, and large bile ducts with inflammatory and obliterative concentric periductal fibrosis, leading to biliary stenosis. Metaplasia, dysplasia, and carcinoma of the gallbladder occur with high frequency in patients with PSC. The metaplasia- displasia-carcinoma sequence observed in the context of PSC is like that proposed for sporadic gallbladder cancer. In a histological study of 72 resected gallbladders in patients with PSC, significant morphological alterations were found: lymphoplasmacytic chronic cholecystitis was present in 49%, pseudopyloric metaplasia in 96%, intestinal metaplasia in 50%, dysplasia in 37%, and adenocarcinoma in 14% of the samples. The close association between gallbladder neoplasia and intrahepatic bile duct neoplasms supports the concept of “field cancerization” in the biliary tract of patients with PSC. Approximately half of patients with PSC have gallbladder abnormalities, and about 25% have stones in the bile duct. In another series of 102 patients with PSC who underwent cholecystectomy, 13% had a gallbladder neoplasm, and of these, 7% had adenocarcinoma and 6% had a benign tumor [42]. As exemplified by PSC, autoimmune diseases likely increase the risk of gallbladder cancer through the exacerbation of biliary inflammation.

4. Diagnosis

Ultrasonography (US) is the first-line approach and a valuable screening tool in patients with gallstone disease, which is known to be the primary risk factor for gallbladder cancer (Figure 3) [43, 44, 45, 46, 47]. However, it has several limitations: (1) it cannot fully stage the tumor, as it does not accurately visualize lymph nodes, peritoneal extension, and distant metastases; (2) it lacks pathognomonic signs, especially in early stages where nonspecific wall thickening can be indistinguishable from adenomyomatosis or chronic cholecystitis, particularly if extensive, considering that gallbladder cancer tends to cause localized thickening [48].

Figure 3.

US: Gallbladder adenocarcinoma.

The evaluation of carcinoembryonic antigen (CEA) has shown utility in the diagnosis of gallbladder cancer. Recent studies have identified three types of glycoproteins (I, II, and III) in the biliary tract, with type I being present in normal epithelium. In cases of chronic inflammatory lesions, glycoprotein I is replaced by types II and III, with the latter being immunologically identical to CEA. However, these results lack statistical significance and cannot be considered useful for early diagnosis [49, 50].

Contrast-enhanced Computed Tomography (CT) has a diagnostic capability for detecting gallbladder tumors with a sensitivity of 88%, specificity of 87%, and overall diagnostic accuracy of 87%. The main indication for using CT in gallbladder cancer is staging, as this modality can demonstrate neoplastic extension to the gallbladder bed and the surrounding liver (in 60% of cases), as well as the presence of regional lymph node metastases, peritoneal metastases, and distant metastases (Figure 4). Angio- CT assesses the degree of vascular infiltration in the portal vein or hepatic artery, which is important for preoperative evaluation. Differential diagnosis with xanthogranulomatous cholecystitis poses challenges due to overlapping features such as gallbladder wall thickening, involvement of adjacent organs including pericholecystic adipose tissue, portal lymph nodes, and the liver. In the diagnosis of gallbladder cancer, differential diagnosis and determination of local tumor extent are crucial. For these purposes, imaging techniques such as Endoscopic Ultrasound (EUS), CT, Magnetic Resonance Imaging (MRI), and Magnetic Resonance Cholangiopancreatography (MRCP) are useful.

Figure 4.

CT: Gallbladder carcinoma with thickened walls capturing contrast medium.

Endoscopic Ultrasound (EUS) has a good sensitivity (92–97%) in differentiating gallbladder cancer from benign conditions [51, 52].

MRI is not a commonly used imaging modality in the diagnostic workup of gallbladder cancer; however, it can provide useful information [53, 54, 55].

MRCP can provide information on the infiltration of the main bile duct and the extent of intracholecystic tumor.

Positron Emission Tomography with Fluorodeoxyglucose (PET-FDG) can be considered as a complementary examination for the detection of non-abdominal metastases, guiding the surgeon towards radical re-intervention [56, 57].

Another valuable diagnostic tool is ultrasound-guided Fine-Needle Aspiration Biopsy (FNAB), which is accurate, rapid, and cost-effective. Unfortunately, gallbladder cancer has a high potential for dissemination, and the risk of tumor seeding along the needle tract is elevated. Laparoscopic experience with incidental gallbladder cancers has confirmed this risk, with reported cases of tumor implantation along trocar tracks or through the umbilicus during gallbladder extraction. Therefore, the answer is clear: biopsy should not be performed. In cases of uncertainty regarding both the nature of the neoplasm and its potential resectability (10–15% of cases), laparoscopic visualization and a supporting trocar allow, in almost all cases, a definitive assessment of the feasibility of radical surgery.

Currently, in the absence of preoperative diagnosis, an extensive intraoperative core needle biopsy with immediate analysis of frozen sections is preferred before initiating radical resection. In cases where granulomatous cholecystitis is frequently present with large calculi and extensive inflammation, limiting the possibility of a simple cholecystectomy, it is advisable to perform cholecystectomy with stone removal only after intraoperative biopsy has confirmed the absence of malignant neoplasms [58].

Finally, regarding laparoscopy, it can be confidently stated that it represents an excellent diagnostic tool for closed abdomen gallbladder cancer. Despite the era of significant technological advancements in diagnostic imaging, there are suggestive signs of neoplasms that can sometimes only be detected through laparoscopic exploration.

5. Staging

To stage gallbladder cancer, various classification systems can be used, all considering the most relevant prognostic factors: tumor type, size, depth of wall infiltration, invasion of adjacent organs, and metastatic spread via blood vessels, lymphatic system, and peritoneum.

The staging system of the Japanese Biliary Surgical Society divides tumors into 4 stages:

1. Stage 1: Cancer confined to the gallbladder capsule.

2. Stage 2: Cancer with lymph node involvement (N1) and/or minimal invasion of the liver/bile ducts.

3. Stage 3: Lymph node involvement (N2) and/or significant invasion of the liver/bile ducts.

4. Stage 4: Presence of distant metastases.

The Nevin classification is widely accepted in the Western world. It considers the stage of the neoplasm and the degree of cellular differentiation. In addition to its diagnostic significance, it also has prognostic value and provides therapeutic guidance by formulating tables with combined numbers for stage and grade. Nevin reported a 5-year survival rate of 21% after cholecystectomy in patients at stages I (intramucosal cancer or carcinoma in situ) and II (invasion of the mucosa and muscular layer), contrasting with poor outcomes in stages III (full-thickness invasion), IV (presence of metastasis in pericystic lymph nodes), and V (hepatic invasion and/or distant metastasis). Donohue et al. modified the Nevin system to include tumors involving the liver adjacent to the gallbladder in stage III and non-adjacent tumors in stage V [59, 60].

However, to date, the most well-known and widely used classification is undoubtedly the TNM classification (Table 1) [61].

Stage	T category	N category	M category	Estimated 5-year survival (%)
0	Tis	N0	M0	80–100
I	T1a (lamina propria)	N0	M0	80–100
	T1b (muscularis)	N0	M0	80–100
II	T2a (peritoneal side)	N0	M0	40–75
	T2b (hepatic side)	N0	M0	28–50
IIIa	T3	N0	M0	8–28
IIIb	T1, T2, T3	N1	M0	8
IVa	T4	N0, N1	M0	7
IVb	Any T	N2	M0	4
	Any T	Any N	M1	0–2

Table 1.

TNM staging according to the Eighth Edition of the AJCC* Manual.

^*

AJCC = American Joint Committee on Cancer.

Source: References [2, 42].

Regarding histopathological grading, we distinguish:

• G1, well-differentiated carcinoma

• G2, moderately differentiated carcinoma

• G3, poorly differentiated carcinoma

• G4, undifferentiated carcinoma.

The AJCC/UICC staging is based precisely on the TNM classification [62]. The main conceptual difference with the Nevin classification is that the latter does not differentiate tumors that invade the muscular layer without invading the liver and does not make a distinction based on tumor size. These two characteristics have significant prognostic significance. Partial or total invasion of the muscular layer is essential considering that the lymphatic drainage of the gallbladder lies between the muscular layer and the serosa. The pre-muscular subserosa is a plane composed of connective tissue, nerve endings, blood vessels, lymphatics, and adipocytes; it is not covered by the serosa in the portion of the gallbladder that is nestled in the liver, but it represents a key element for neoplastic dissemination, considering that in most cholecystectomies for cholelithiasis, the subserosal plane is the easiest for dissection. In incidental tumors that have invaded the muscular layer, this allows an open pathway for tumor metastasis through the lymphatic route [59].

6. Treatment

Gallbladder cancer treatment depends on several factors, such as the stage of cancer, overall health, and patient’s preference [63]. Surgical resection is the primary treatment for localized gallbladder cancer, which involves removing the gallbladder, surrounding lymph nodes, and portions of the liver and bile ducts [64]. A radical cholecystectomy is generally recommended, but a laparoscopic cholecystectomy may be appropriate for select patients with early-stage cancer who have no invasion into surrounding tissues [65].

For patients with advanced or metastatic disease, a multidisciplinary approach is necessary, which may include systemic chemotherapy, radiation therapy, or a combination of these modalities [66]. Chemotherapy regimens for gallbladder cancer may include gemcitabine and cisplatin, or other combinations of cytotoxic agents [67]. The use of immunotherapy, such as immune checkpoint inhibitors, has shown promise in early clinical trials but requires further research to understand the role in the treatment of gallbladder cancer [68]. Palliative measures, such as biliary stenting, pain management, and nutritional support, may also be used to manage symptoms and improve quality of life for patients with advanced gallbladder cancer [64].

The surgical management of gallbladder cancer depends on several factors, including the extent and location of the tumor, the patient’s overall health status, and the experience of the surgeon [64]. Surgical removal of the gallbladder (cholecystectomy) is the primary treatment option for early- stage gallbladder cancer that is confined to the gallbladder and has not spread to nearby lymph nodes or organs [65]. Laparoscopic (Figure 5) or robotic-assisted cholecystectomy is associated with less pain, shorter hospital stays, and faster recovery times compared to open surgery [69].

Figure 5.

VLS colecystectomy.

For more advanced gallbladder cancer, surgery may involve removal of the gallbladder, portions of the liver, and nearby lymph nodes. This is known as a radical cholecystectomy and may be done using an open or minimally invasive approach (Figure 6) [64].

Figure 6.

Laparoscopic vs open procedure.

Despite the challenges, surgical management remains the most effective treatment option for localized gallbladder cancer, and advances in surgical techniques, systemic therapies, and supportive care have improved outcomes for patients [70]. The success of surgery depends on several factors, including the stage of the cancer, the experience of the surgical team, and the patient’s overall health status [64]. The treatment of gallbladder cancer requires a multidisciplinary approach, with close collaboration between surgeons, medical oncologists, radiation oncologists, and other specialists [66]. The goal of treatment is to maximize the chances of cure while minimizing treatment-related side effects and optimizing quality of life for the patient [70].

7. Prognosis and follow-up

The prognosis for gallbladder cancer varies depending on the stage of the cancer at diagnosis, with earlier stage cancers having a better prognosis than more advanced stage cancers. Other factors that can impact prognosis include the size and location of the tumor, the patient’s overall health status, and the presence of other medical conditions [1].

For patients with early-stage gallbladder cancer that has not spread beyond the gallbladder, the five-year survival rate is around 80%. However, for patients with more advanced stage cancer that has spread to nearby organs or lymph nodes, the five-year survival rate is much lower, around 5–10% [2].

In chronic carriers of large gallstones, the best prevention for gallbladder cancer is cholecystectomy, as shown in a case-control study of 81 patients in 1983 by Andrew K. Diehl.

After surgery, patients with gallbladder cancer will require close monitoring to detect any signs of recurrence. This may involve regular imaging tests, such as CT scans or ultrasounds, as well as blood tests to monitor for tumor markers. The frequency and duration of follow-up will depend on the stage of the cancer, the patient’s overall health status, and other factors [1].

In addition to imaging and blood tests, follow-up for gallbladder cancer may also involve monitoring for symptoms such as jaundice, abdominal pain, and weight loss, which may indicate recurrence or metastasis. Patients should also be counseled on lifestyle modifications, such as maintaining a healthy diet and exercise routine, and avoiding tobacco and excessive alcohol consumption, to help reduce the risk of recurrence [71].

In cases where the cancer has spread beyond the gallbladder, additional treatments such as chemotherapy, radiation therapy, or targeted therapy may be recommended. These treatments may be used before or after surgery, depending on the specific circumstances of the patient’s case [1].

Overall, the prognosis for gallbladder cancer can be challenging, particularly in cases where the cancer has already spread beyond the gallbladder. However, with appropriate treatment and close follow-up, many patients can achieve good outcomes and maintain a good quality of life [2].

8. Conclusions

In conclusion, gallbladder cancer is a rare but serious malignancy that presents many challenges for patients and healthcare providers. Early detection is key to improving outcomes, and surgical resection remains the mainstay of treatment for most patients. However, the complex anatomy and physiology of the gallbladder and biliary system can make surgical management of gallbladder cancer difficult, requiring specialized expertise and careful planning [1].

Despite these challenges, recent advances in diagnostic and imaging technologies, as well as in surgical and non-surgical treatment options, offer hope for patients with gallbladder cancer. With ongoing research and improved understanding of the pathogenesis and molecular biology of this disease, new targeted therapies and personalized treatment approaches may become available in the future [2].

In the meantime, it is important for patients with gallbladder cancer to receive multidisciplinary care from a team of experienced healthcare providers, including surgeons, oncologists, radiologists, and other specialists as needed. Through collaboration and a patient-centered approach to care, we can continue to make progress in the fight against gallbladder cancer and improve outcomes for patients [1].