Diagnostic and Management Issues in Gallbladder Carcinoma

This paper by Abi-Rached and Neugut provides an overview of thediagnosis and treatment of gallbladder carcinoma, a rare, yetfrustratingly difficult disease to manage [1]. Overall, we agreewith the risk factors described in this review. We would add that,in addition to chronic cholecystitis, porcelain gallbladder, andretained gallbladder (secondary to cholecystostomy), cholecysto-entericfistulas have also been associated with a higher incidence ofgallbladder carcinoma [2,3] Patients with ulcerative colitis areknown to be at higher risk for cholangiocarcinoma, and there isalso some evidence that these patients have an increased riskof gallbladder cancer.

Benign adenomas of the gallbladder have been described as incurringa slightly increased risk, but this evidence is not very convincing.In a recent paper from Chile, where a high incidence of benignand malignant gallbladder disease has been noted, a definite associationbetween metaplasia in the specimen and the age of the patientwas reported [4]. In addition, severe hyperplasia is associatedwith higher incidences of dysplasia and carcinoma in situ, inferringa progression from hyperplasia and dysplasia to carcinoma in situ.

Presentation

As mentioned in the Abi-Rached/Neugut review, patients with gallbladdercancer often present with classic symptoms of benign gallbladderdisease, with persistent, gnawing pain in the right upper quadrantas the disease progresses. In one large series, the average durationof symptoms prior to presentation was 3 months [3]. The presenceof jaundice is an indicator of advanced, unresectable disease.Ultrasound is the most sensitive and informative initial test,as most patients being evaluated have benign gallbladder disease;however, CT provides better anatomic detail in evaluating theliver and porta hepatis for adenopathy in patients with advanceddisease. Unfortunately, current imaging techniques too often failto detect small lesions such as peritoneal implants.

The role of surgery in the treatment of gallbladder carcinomacontinues to be reevaluated in the surgical literature. Most authorsagree that simple cholecystectomy is adequate therapy when tumorsare confined to the mucosa or barely penetrate the muscularispropria layers [2]. Survival in this select group ranges from60% to 90%, and in several series approaches 100%. Unfortunately,only 5% to 10% of cases present with asymptomatic gallbladdercancer and have limited invasion of the gallbladder wall.

Radical surgery has been shown to improve survival in selectedpatients when disease extends beyond the muscularis and into theserosa (or into the liver). In a recent German series of 113 patients,the median survival was 14 months after curative resection and5.8 months after palliative resection, compared with 3.6 monthsafter exploration alone. In another series, from the Mayo Clinic,that included 111 patients, the median survival after radicalcholecystectomy was 3.6 years vs 8 years after simple cholecystectomy.In this series, survival was related to stage, ranging from 100%in patients with stage I (mucosal) to 25% in patients with stagesIII and IV disease (muscularis/serosal invasion).5 In severalseries, patients with disease limited to invasion of the muscularis/serosa,survival was markedly better with radical cholecystectomy (90%)than with simple cholecystectomy (41%) [6].

Although survival in patients with stage III (into serosa) orstage IV (nodal disease) is poor in Western series of patients(less than 10%), survival in Japanese series is reported to be20% [6]. This may represent major genetic differences, as wellas possible therapeutic differences. In a large Japanese seriesthat included 2,567 patients, the 5-year survival for patientswith stage III and stage IV disease was 20% [6]. As expected,survival was significant lower in patients with transmural tumorinfiltration or nodal metastasis than in those with cancer confinedto the gallbladder wall.

Achieving Local Control

The goal of radical cholecystectomy is to provide adequate controlof local disease. Gallbladder carcinomas spread most commonlyby direct hepatic extension through the periportal lymphatics.The lymphatics drain into the cystic node and the common ductnodes, into the pancreatic, duodenal, celiac axis, and para-aorticnodes. Therefore, an adequate resection requires dissection ofnodes along the cystic duct, portal vein, and common duct, andperipancreatic area. In addition, most recommend resection ofa 3 cm to 4 cm margin of normal hepatic parenchyma underlyingthe gallbladder bed (Segment IVB, V), removing the specimen enbloc from the peritoneal cavity. The margins are marked with radiopaqueclips, should external beam radiotherapy be considered postoperatively.

Evaluation of prognostic indicators provides for a more rationalapproach to reoperation on patients who have undergone cholecystectomy.In a recent study, immunohistochemical staining with a monoclonalantibody against CA 19-9 was used to predict lymph node spreadof cancer. In 23 patients with gallbladder cancer, CA 19-9 waspresent in pathology specimens from all 23 patients. Twelve samplesshowed staining in the connective tissue stroma adjacent to cancercells, while the remaining 11 did not show any stromal staining.Lymph node metastasis was found in 75% of the patients with stromalstaining, and only 18% of the patients without stromal staining[7,8].

In another study, the role of the c-erb B-2 gene and proteinexpression and tumor invasiveness were examined in 43 patientswith gallbladder carcinoma, using immunohistochemistry and thepolymerase chain reaction [9]. Fourteen of the 43 cases showedpositive immunoreactivity and c-erb B-2 protein overexpression,although no statistically significant correlation was found withtumor differentiation, invasion, and lymph node metastasis. Furtherstudies are needed to help clinicians identify those patientswho would most benefit from radical surgery.

Preventing Iatrogenic Spread

Finally, we should mention the potential for iatrogenic disseminationof gallbladder cancer during laparoscopic surgery [5]. Since 1992,14 cases have been reported in the literature. In one series,ten patients diagnosed with gallbladder cancer via laparoscopywere further explored. In three of the ten, a subsequent radicalresection was performed, with curative intent. Four patients hadintraperitoneal spread, not present at original laparoscopy, whichprecluded potentially curative resection. In two of these patients,tumor growth was noted within the laparoscopy tract. The medianinterval between initial exploration and reexploration was 30days. These data suggest that laparoscopic surgery should notbe undertaken if radiologic or clinical criteria suggest the diagnosisof gallbladder cancer. Furthermore, if this diagnosis is suspectedon visual inspection during laparoscopy, the procedure shouldbe abandoned.

In conclusion, in patients who are found to have carcinoma invadingmucosa or the muscular coat, cholecystectomy alone should suffice.If there is extension into or through the serosa, a radical cholecystectomyshould be done after careful imaging to exclude metastases tothe liver or beyond.

References:

1. Abi-Rached B, Neugut A: Diagnostic and management issues ingallbladder carcinoma. Oncology, 9(1):19-24, 1995.

2. Wanebo HJ, Vezeridis MP: Carcinoma of the gallbladder. J SurgOncol (suppl 3):134-139, 1993.

3. Wanebo HJ, Castle WN, Fechner RE: Is carcinoma of the gallbladdera curable lesion? Ann Surg 195:629-631, 1982.

4. Gall FP, Kockerling F, Scheele J, et al: Radical operationsfor carcinoma of the gallbladder: Present status in Germany. WorldJ Surg 15:328-336, 1991.

5. Duarte I, Llanos O, Domke H, et al: Metaplasia and precursorlesions of gallbladder carcinoma. Cancer 72(6):1878-1884, 1993.

6. Shirai M, Moshida K, Tsukada K: Inapparent carcinoma of thegallbladder. An appraisal of a radical second operation aftersimple cholecystectomy. Ann Surg 215:326-331, 1991.

7. Wanebo HJ: Carcinoma of the gallbladder, in Wanebo HJ (ed):Hepatic and Biliary Cancer, pp 431-445. New York, Marcel Dekker,1987.

8. Ohta T, Nagakawa T, Fonseca L, et al: Stromal distributionof CA 19-9 as a predictor of lymph node metastases in gallbladdercancer without serosal invasion. Oncology (Europe) 51(3):238-243,1994.

9. Suziki T, Takano Y, Kakita A, et al: An immunohistochemicaland molecular biological study of c-erb B-2 amplificationand prognostic relevance in gallbladder cancer. Pathol Res Pract189(3):283-292, 1993.