Gallbladder Cancer

David Bentrem

Yuman Fong

INDICATIONS/CONTRAINDICATIONS

Gallbladder carcinoma (GBC) is the most common biliary epithelial malignancy, with an estimated 9,520 new cases and 3,340 deaths per year. The incidence steadily increases with age, reaching a maximum in the seventh decade of life. GBC predominantly affects women (75% to 85%) and is more commonly found in Native, Alaskan, or Hispanic Americans. There is, in addition, an association between the presence of gallstones and GBC, though this relationship is not well understood. Interestingly, size of gallstones is also a risk factor; patients with stones greater than 3 cm are 10 times more likely to develop GBC compared with patients with subcentimeter-sized gallstones. While cholelithiasis and its associated repeated inflammation may contribute, this relative risk and the influence of environmental toxins (carcinogens in tobacco, diet, etc.) or hormones remain unclear. This disease’s insidious nature and typically late presentation place it among the most lethal of invasive neoplasms. Gallbladder cancer spreads early by lymphatic or hematogenous metastasis and by direct invasion into the liver. While surgery may well be curative at early stages, both surgical and nonsurgical treatments remain largely unsuccessful in patients with more advanced disease.

Indications

Broadly, surgical therapy is indicated for localized disease that is limited to the gallbladder, liver bed, and regional lymph nodes (Fig. 27.1A, B). Operative strategies differ, however, depending on depth of invasion of the primary lesion and the presence of lymphadenopathy concerning for metastasis.
Generally, T1a lesions, defined as tumors limited to the gallbladder mucosa without extension to muscular layers of the wall, can be sufficiently treated with cholecystectomy alone without further radical surgical resection. Patients whose disease extends into the muscular layers of the gallbladder and beyond, however, require a more aggressive surgical approach.
For T1b, T2, or T3 lesions with (or without) associated regional adenopathy, en bloc resection with regional lymphadenopathy is appropriate. Extension of disease proximally to the bile duct may require bile duct excision with reconstruction for biliary drainage. For patients with resected T2 lesions, 30% have been found to have nodal disease and 16% metastatic disease. With resected T3 lesions, 58% were found to
have nodal disease and 42% peritoneal metastases. This leads to a low likelihood of completed resection (27%) for patients with clinically staged T3 tumors.
Gallbladder wall polyps are not uncommon, and polypoid lesions of the gallbladder are frequently noted on abdominal ultrasonography. The clinical relevance of this finding, however, is not entirely clear. The surgeon’s suspicion of growth as well as the evolution of dysplasia and eventual invasive carcinoma serves as the basis for recommending close surveillance, or even resection, for certain polypoid lesions. Concerning features include solitary, large, immobile, or changing lesions. Traditionally, gallbladder polyps greater than 1 cm in size were thought to be at a higher risk for containing GBC foci (Table 27.1).
Calcifications of the gallbladder (leading to the oft-used term “porcelain gallbladder”) have been viewed as a risk factor for developing GBC (Table 27.1). Polk, in 1966, was one of the original proponents of this hypothesis and pointed to two pieces of evidence to substantiate it. More recent literature more specifically defined gallbladder calcifications. A report by Stephen and Berger explicitly classified gallbladder calcifications as intramural (n = 17) or selective mucosal (n = 27). They reported that of gallbladder specimens of the intramural type, no cases of adenocarcinoma were identified, whereas selective mucosal calcifications heralded a 7% malignancy rate.
With respect to extent of disease related to hepatic parenchyma, critical attention must be given to invasion of the hepatic arteries and ducts. Notably, invasion of the right hepatic artery or duct is not a contraindication to aggressive surgical therapy; while these findings may necessitate a right (or even extended right) hepatectomy, adequate reconstruction can be accomplished.

Figure 27.1 A: Regional lymph nodes of the gallbladder; B: N1 disease is defined as metastasis to regional lymph nodes.

Contraindications

Distant metastases
Extensive, bilateral liver involvement
Local extension of disease involving the left hepatic artery, left hepatic duct, or the confluence of the portal vascular or biliary structures is indicative of more extensive disease less likely controlled by surgery (Fig. 27.2A). Similarly, if a tumor progresses distally toward the duodenum and pancreas with (perhaps) invasion of one of those structures, a Whipple procedure may be considered but long-term disease control is doubtful (Fig. 27.2B).

TABLE 27.1 Series of Gallbladder (GB) Calcifications and Polyps

Authors (y)	N	Entity Studied (Calcification or Polyp)	Size, Lesion Characteristics	Association or Incidence of GBC	Conclusion
Kim et al. (2009)	9 (of 3,159 inspected)	Calcifications	Pathologically proven porcelain gall bladder	No porcelain GB had GBC; no patients with GBC had calcification	No association between porcelain GB and GBC
Ito et al. (2009)	417	Polyps	94% of polyps ≤10 mm, 7% >10 mm	No cases of invasive GBC in 80 surgical specimens	Risk of invasive cancer in GB polyp is extremely low
Stephen and Berger (2001)	150 GBC (of 25,900 inspected)	Calcifications	Selective mucosal n = 27, intramural n = 17	7% of selective mucosal with GBC, none with intramural	Pattern of calcification determines cancer risk
Towfigh et al. (2001)	103 (of 10,741 inspected)	Calcifications (“porcelain” GB)	Partial calcification of wall (n = 15) and GBC (n = 88)	No porcelain GB had GBC; no patients with GBC had calcification	Porcelain GB/calcifications not associated with GBC
Terzi et al. (2000)	100	Polyps	74% benign (20% adenomas, 15% adenomatous hyperplasia)	26% rate of malignancy	Risk factors for GBC are age >60, size >10 mm, coexistence of gallstones
Mainprize et al. (2000)	38	Polyps	11/34 patients with polyps pathologically proven; 7/11 benign cholesterol polyps	All neoplastic disease (n = 4) arose in polyps >10 mm	Should perform cholecystectomy for polyps >10 mm
Kubota et al. (1995)	72	Polyps	47/72 cholesterol polyps, GBC in 16/72	88% of GBC in polyps >18 mm, 56% were sessile	Polyps <18 mm potentially early stage, >18 mm likely advanced
Koga et al. (1988)	32 (of 411 resected specimens)	Polyps	Primarily examined age, size and type (most were cholesterol polyps)	88% of malignancy in polyps >10 mm, 75% in patients >60 y	Risk factors for GBC are age >60, size >10 mm
GBC, gallbladder carcinoma.

Figure 27.2 A: Illustration of a gallbladder cancer extending into the porta hepatis; B: Illustration of a gallbladder cancer involving adjacent extrahepatic organs (duodenum, pancreas, colon).

Lymph node metstases outside the region of the porta hepatis. Nodal spread beyond the hepatoduodenal ligament (celiac, retropancreatic, aortocaval) generally represents metastatic disease.
Significant comorbidities.

PREOPERATIVE PLANNING

Diagnosis

There is no single clinical physical examination finding, laboratory value, or imaging modality that can unequivocally diagnose early GBC, and rarely are any of these approaches given consideration preoperatively. Symptoms of invasive GBC are notoriously vague and nonspecific. Right upper quadrant pain primarily associated with benign biliary disease may be the first and only presenting symptom. Alternatively, a smaller percentage of GBC patients may present with obstructive jaundice secondary to local disease progression and obstruction of biliary outflow tracts. Other physical signs are limited. The usual clinical scenario is that of incidentally found GBC at the time of cholecystectomy. Approximately 1% of cholecystectomy specimens contain evidence of invasive disease, and this rate is significantly higher in patients greater than 70 years. Mass lesions, focal thickening, or mucosal calcifications on abdominal imaging should raise suspicion of an underlying malignancy.

Clinical Staging

Cancers of the gallbladder are ultimately pathologically staged according to their depth of penetration and extent of spread. Clinical staging for GBC consists of imaging modalities as well as pathologic specimens when available from prior surgical resections.

For GBC discovered by the pathologist incidentally, subsequent staging depends on pathologic tumor (T) stage. Extent of locoregional disease is directly correlated with the T stage of GBC, with more invasive lesions exhibiting higher rates of lymph node and distant metastases. T stage classification depends on the depth of tumor penetration into the wall of the gallbladder, on the presence of tumor invasion into the liver, hepatic artery, or portal vein, and on adjacent organ involvement. T1a lesions, those that have not breached the muscular layers, require no further staging or treatment. Accurate staging for more advanced, resectable tumors requires that all hilar lymph nodes be removed and analyzed. The hilar nodes include the lymph nodes along the common bile duct (CBD), hepatic artery, portal vein, and cystic duct.

For any tumor that has invaded the muscular layer or beyond, additional postoperative imaging is mandatory for clinical staging. This should include high-resolution 3D imaging of the chest, abdomen, and pelvis, specifically evaluating regional lymphadenopathy or any evidence of distant metastases. In addition, because even sophisticated imaging may understage disease and underestimate the propensity to seed the peritoneal surfaces after the prior operation, staging laparoscopy should be strongly considered. A minority of patients may present not with a tissue diagnosis, but with either (a) an incidentally found mass discovered while imaging the patient for other reasons, or (b) jaundice. Under these circumstances, in addition to the imaging studies described above, one should obtain a complete blood count (CBC), liver function tests, consider adding CA19-9 and carcinoembryonic antigen (CEA) serum markers, and again strongly consider staging laparoscopy, depending on results of the aforementioned tests.

Imaging

Ultrasonography is the most frequently utilized imaging modality for biliary pathology. Perhaps the only caveat of this approach is the user-dependent nature of both acquiring and analyzing the imaging. For GBC, ultrasound has reported 70% to 90% sensitivity

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