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Gallbladder cancer (GBC) is a rare, aggressive, and highly fatal malignancy. It is the most common tumor of the biliary tract and is distinguished from other biliary tract cancers on the basis of its clinical and biologic characteristics. Approximately 5000 new cases are diagnosed annually in the United States. In most cases, the diagnosis is an incidental finding in patients undergoing laparoscopic cholecystectomy for exploration for gallstones. Advanced GBC is associated with a poor prognosis and a 5-year survival rate of 15-20%; accordingly, diagnosis of early-stage disease is critical for improving patient outcomes.[1-4]
Image from Anatomical Travelogue | ScienceSource.
Bile duct cancers, also known as cholangiocarcinomas or cholangiocellular carcinomas (CCCs), are rare malignancies that can arise anywhere along the biliary tract. This type of cancer is usually lethal because of its aggressive nature and its typical presentation at an advanced stage. CCCs are found in three anatomic regions: intrahepatic, extrahepatic perihilar (hilar; shown), and distal extrahepatic.[5] Cancers in these different areas can cause different symptoms. Intrahepatic cancers develop in the smaller bile duct branches inside the liver. Perihilar tumors (also called Klatskin tumors) are the most common CCCs and arise from the bifurcation (hilum) of the right and left hepatic ducts. Distal extrahepatic tumors are located from the upper border of the pancreas to the ampulla. The Bismuth classification is used to differentiate patterns of involvement of the hepatic ducts. Bile duct cancers can be classified on the basis of cell type; more than 90% of these tumors are ductal adenocarcinomas. Many patients present with unresectable or metastatic disease, leading to a poor prognosis.[5-7] All three types of CCC are slow-growing and are characterized by a high rate of local invasion, mucin production, and a tendency to spread along nerves.
Image courtesy of Wikimedia Commons.
Cancer of the ampulla of Vater is uncommon; ampullary carcinomas account for only about 0.5% of all gastrointestinal (GI) malignancies.[8] However, it is often life-threatening unless properly diagnosed, staged, and surgically treated. This cancer arises within 2 cm of the distal end of the common bile duct (CBD), passing through the wall of the duodenum and the ampullary papilla (shown).[9] It may derive either from the duodenal side of the ampulla or from the intra-ampullary portion of the papilla. There are two main histologic variants of ampullary cancer, specified according to the epithelium of origin: intestinal and pancreatobiliary.[10] The clinical behavior of the intestinal variant is similar to that of its duodenal counterpart, whereas pancreatobiliary tumors are more aggressive and resemble pancreatic adenocarcinomas. In regard to patient survival, the intestinal-type ampullary adenocarcinoma has a more favorable prognosis.[11]
Image courtesy of Wikimedia Commons.
The image in the slide shows a gross slice of liver with attached gallbladder obliterated by tumor. Tumor invasion of adjacent liver parenchyma is seen.
Which of the following statements about GBC is not true?
Image courtesy of WikiDoc.
Answer: B. Elevated alkaline phosphatase (ALP) and bilirubin levels are often found with early-stage disease.
Elevated bilirubin and ALP levels are commonly found with more advanced disease. Laboratory studies are generally nonspecific for early GBC.[4] Patients with early invasive GBC are most often asymptomatic. Early-stage disease is most often incidentally discovered during laparoscopic cholecystectomy (shown), which is performed during exploration for presumed symptomatic cholelithiasis or acute cholecystitis.[2]
Image courtesy of Wikimedia Commons.
The image in the slide shows a gallbladder adenocarcinoma from an elderly man. A gray circle of tumor tissue replacing the normal gallbladder wall, intraluminal gallstones, and tumor infiltration into adjacent liver tissue are visible.
Which of the following is not a risk factor for the development of GBC?
Image from Dr Gladden Willis | Visuals Unlimited.
Answer: F. All of the above are risk factors.
Risk factors that share a common characteristic of chronic gallbladder inflammation have been associated with GBC.[2] Certain medications (eg, methyldopa and oral contraceptives) have been implicated in biliary carcinogenesis, though no conclusive evidence has been found.[12] Large gallbladder polyps are more likely to contain foci of invasive cancer, and some studies suggest a correlation between the presence of gallbladder polyps and the risk of GBC.[13] GBC can appear as large polyps. The image in the slide shows multiple polyps within a resected gallbladder.
Image courtesy of Wikimedia Commons.
The ultrasonogram in the slide shows heterogeneous thickening of the gallbladder wall (red arrows) in a 71-year-old woman. The diagnosis was primary papillary adenocarcinoma of the gallbladder. Gallbladder thickening has a wide differential diagnosis that can include acute and chronic cholecystitis, xanthogranulomatous cholecystitis, and adenomyomatosis. Systemic diseases such as acute hepatitis, portal hypertension, and congestive cardiac failure can also present with gallbladder-wall thickening.[1] It is important to evaluate the patient appropriately for suspected GBC during the early stage of the disease.
Image courtesy of Medscape.
A 37-year-old woman presents with persistent upper abdominal pain of 2 weeks' duration. Physical examination reveals mild painless jaundice and a palpably enlarged gallbladder that is nontender in the right upper quadrant (Courvoisier sign). The patient denies experiencing fever or weight loss. She currently takes oral contraceptives daily and ibuprofen as needed for abdominal pain. US reveals an immobile echogenic focus arising from the gallbladder wall, consistent with the presence of a gallbladder polyp. (The sonogram in the slide shows a polypoidal mass arising from the gallbladder wall of a pediatric patient.)
Which of the following is the most appropriate next step in the evaluation of this patient?
Image courtesy of National Institutes of Health.
Answer: C. Computed tomography (CT).
Although US is highly sensitive for tumor detection at advanced stages, it is inappropriate for the diagnosis of early lesions and is unreliable for staging. On US, gallbladder carcinoma can have a more subtle appearance (eg, a focal or diffuse asymmetric wall thickening or an intraluminal polyp).[1] CT or MRI is more widely used for characterizations of potentially malignant gallbladder lesions and can be used to evaluate the extent of metastatic disease.[14] CT scans may be useful in patients with upper abdominal pain and can demonstrate tumor invasion outside the gallbladder and identify metastatic disease elsewhere in the abdomen or pelvis. Liver invasion occurs in 60% of cases, and the combination of CT and US provides accurate details of disease extension.[4] The CT scan in the slide shows liver invasion in a patient with SCC of the gallbladder.
Image courtesy of Medscape.
The prognosis for patients with GBC is correlated with staging (shown), as determined in accordance with the well-known tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC).[15] In the seventh edition of the American Joint Committee on Cancer Staging Manual, significant changes were introduced to include the designation of cystic duct involvement, the distinction between involvement of regional hilar lymph nodes and that of distant regional nodes (celiac, periduodenal, peripancreatic, and superior mesenteric nodes), and the reclassification of unresectable locally advanced T4 tumors as stage IV disease.[1,15] Stage I disease without muscular involvement should be curable with a simple cholecystectomy. Stage IV disease generally is not surgically curable. The median survival is 2-4 months.[4]
Table adapted from AJCC Staging Manual, 7th ed.[15]
Surgical treatment is curative for lesions localized to the mucosa and submucosa, but these represent only about 16% of all GBCs.[16] Patients diagnosed with T1b, T2, and T3 tumors who do not have distant metastatic disease and who are otherwise fit for a major operation should be treated by means of extended resection with curative intent.[1]
For a patient who is diagnosed with a T1b tumor (invasion of muscle layer; shown) and has no distant metastatic disease, which of the following is the most appropriate next step in treatment?
Image courtesy of Cancer Research UK uploader | Wikimedia Commons.
Answer: B. Resection of liver segments IVb and V and portal lymph node dissection.
T1a GBCs can be treated with cholecystectomy alone. T1b tumors are treated with resection of liver segments IVb and V and portal lymph node dissection; bile duct resection is sometimes required to achieve a negative margin. T2 and T3 lesions are also treated with hepatic resection and portal lymph node dissection, but extended right hepatectomy may be necessary to achieve negative margins. Surgery with curative intent is inappropriate for T4 lesions (invasion of hepatic artery, main portal veins, and multiple adjacent structures). Instead, palliative treatment such as drainage or chemotherapy for unresectable GBC should be considered.[16-18] The image in the slide is a hematoxylin-eosin (H&E) stain showing lymphatic invasion by gallbladder adenocarcinoma, incidentally found in a cholecystectomy specimen.
Image courtesy of Wikimedia Commons.
Treatment options for advanced and unresectable tumors (shown) are limited, and the prognosis is typically poor. Palliative treatment should be discussed in an attempt to improve the patient's quality of life and alleviate the symptoms of the disease.
Which of the following is not a potential treatment that a multidisciplinary tumor board should consider for a patient with advanced GBC?
Image courtesy of Cancer Research UK uploader | Wikimedia Commons.
Answer: E. All of the above are potential treatments.
Because of the rarity of GBC, there are currently no clearly defined standards for chemotherapy and palliative treatment. Patients should be encouraged to participate in clinical trials.[4] The combination of gemcitabine and cisplatin has been found to be effective for the treatment of patients with unresectable or metastatic disease.[19] Combination chemotherapy has demonstrated a survival advantage over single-agent chemotherapy.[20] The image on the left is an initial staging CT scan, revealing an extensive gallbladder mass before the initiation of chemotherapy. The image on the right is a follow-up CT scan obtained after the halfway point of the fourth cycle of gemcitabine-cisplatin chemotherapy, revealing no sizable gallbladder mass.
Images (adapted) courtesy of Rho YS et al.[21]
Although GBC is not common, mortality is high as a consequence of late presentation of symptoms and delayed diagnosis of this aggressive disease.[22] Improvements in early-stage diagnosis, as well as better treatment options and more clinical trials, are necessary to improve patient outcomes.
Data from Gagner M et al.[22]
The image in the slide is a perihilar (Klatskin) tumor seen during ERCP. Wires are placed in the right and left biliary systems, and both parts are injected with contrast. The lack of contrast in the area of the confluence is clearly visible.
With regard to bile duct cancer (ie, cholangiocarcinoma or cholangiocellular carcinoma [CCC]), which of the following statements is not true?
Image courtesy of Wikimedia Commons.
The image in the slide shows a distal CBD tumor removed in the course of a Whipple procedure. The tumor measured 1.2 cm in diameter.
Which of the following is not a risk factor for developing CCC?
Image courtesy of Medscape.
Answer: G. All of the above are risk factors.
Answers A through F have all been linked to the development of bile duct cancer. Primary sclerosing cholangitis is the most common risk factor.[24-26] The image in the slide shows dilatation of the proximal biliary tree and a narrowed distal CBD as seen via ERCP.
Image courtesy of Medscape.
The poor survival prognosis is a result of diagnosing CCC after it has become too advanced for curative surgical treatment. A proposed algorithm for detecting early bile duct cancers in clinical practice is as follows[27]:
The image in the slide is an operative photograph of a choledochojejunostomy, revealing a bile duct that is large enough to permit anastomosis to the bowel.
Image courtesy of Medscape.
A 66-year-old patient presents with yellowing of the skin and sclera and with complaints of persistent itching, frequent diarrhea, and progressive weight loss. The patient has a history of prolonged alcohol consumption. Laboratory studies indicate marked elevations of serum bilirubin, ALP, cancer antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Abdominal US reveals bile duct dilatation. CT is ordered, with the results shown in the slide.
Which of the following is not among the common signs and symptoms of CCC?
Image courtesy of Wikimedia Commons.
Answer: C. Palpable lymphadenopathy.
Palpable lymphadenopathy is considered to be an uncommon symptom of CCC. Hepatomegaly may be noted in as many as 25% of patients.[5] Jaundice is the most common clinical manifestation of CCC, usually followed by itching. The image in the slide depicts bilirubin metabolism; obstructive jaundice results from elevation of direct/conjugated hyperbilirubinemia with an increase in urinary bilirubin and a decrease in urobilinogen.
Image courtesy of Rim Halaby | WikiDoc.
The patient is diagnosed with distal extrahepatic bile duct cancer. Biopsy is performed, and the lesion is determined to be a hilar CCC. The images in the slide represent contrast-enhanced CT (left column), fused PET-CT (middle column), and PET (right column) findings in this setting. A fluorodeoxyglucose (FDG)-avid primary tumor can be seen (top row, a), along with unsuspected nodal (middle row, b) and peritoneal (bottom row, c) metastases.
Which of the following should not be considered by a multidisciplinary tumor board as potential treatment for this patient?
Image courtesy of National Institutes of Health.
Answer: C. Hepatectomy or Whipple procedure.
Hepatectomy and other extensive curative operations are indicated only for patients with anatomically resectable tumors. This patient presented with a tumor that is considered unresectable because of liver metastases and vascular invasion. Answers A, B, and D are all palliative therapies and thus can be considered for recurrent, metastatic, or unresectable extrahepatic bile duct cancer.[28] Criteria for resectability include absence of liver metastases, absence of carcinomatosis, and absence of vascular invasion. If the tumor is limited to the bifurcation of the hepatic ducts or a single lobe of the liver or if it involves the portal vein or hepatic artery on the same side, the lesion may be resectable.[24] Complete surgical resection of the bile duct tumor is associated with a survival benefit, and it is the only option for curative intent.[29,30] The image in the slide is of a resected Klatskin tumor involving the intrahepatic bile ducts after a right hepatectomy.
Image courtesy of Wikimedia Commons.
Image A in the slide is a fused PET-CT scan of a 68-year-old woman with a common genetic aberration (KRAS wt) who has been diagnosed with intrahepatic CCC. Image B is an unenhanced CT scan demonstrating multiple FDG-avid liver metastases. After 3 months of erlotinib therapy, axial fused PET-CT (image C) and unenhanced CT (image D) show decreased FDG avidity and slightly decreased size of metastases. Patients can be referred to appropriate clinical trials on the basis of their mutational profiles.
Which of the following agents is not actively used in the treatment of bile duct cancer?
Image courtesy of National Institutes of Health.
Answer: B. Paclitaxel.
Chemotherapy is indicated for patients with unresectable tumors. Cisplatin, 5-FU, capecitabine, oxaliplatin, and gemcitabine can all be used to treat CCC, either alone or in combination. Paclitaxel is used to treat ovarian, breast, and non-small cell lung cancer; it has shown no activity against biliary tract tumors.[31] Because of the limited data available on bile duct cancer and the complexity of this rare disease, a multidisciplinary approach with multiple treatment options should be considered.[32,33] The image in the slide is a gross specimen of an intrahepatic CCC.
Image courtesy of Wikimedia Commons.
The image in the slide is a high-magnification immunohistochemical stain of a well-differentiated periampullary adenocarcinoma.
Which of the following statements regarding cancer of the ampulla of Vater is not true?
Image courtesy of Wikimedia Commons.
Answer: C. The disease is more prevalent in women.
According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, ampullary cancer is more common in men.[8] Jaundice is the presenting symptom in 73% of patients who undergo resection and in 80% of those who do not. Progressive weight loss is the second most common symptom.[34,35] It has been found that tumor budding has a stronger prognostic correlation than either local tumor invasion (T stage) or lymph node metastasis, two established parameters typically incorporated into surgical pathology reports.[36] The image in the slide is an endoscopic view of an ampullary carcinoma.
Image courtesy of David M. Martin, M. D. / Science Source.
Ampullary tumors present at an earlier stage than periampullary tumors. Their strategic location may cause early biliary obstruction with jaundice, biliary colic, bleeding, or pancreatitis.[37,38] The images in the slide show a tumor at the ampulla of Vater as seen on (A) magnetic resonance cholangiopancreatography (MRCP), (B) EUS, and (C) duodenoscopy.
A 58-year-old man presents with obstructive jaundice, progressive weight loss, and idiopathic pancreatitis. Laboratory study reveals an elevated serum bilirubin level. The clinical presentation leads to ultrasonography, which confirms extrahepatic biliary obstruction.
Which of the following is the most appropriate next step in the evaluation of this patient?
Images courtesy of National Institutes of Health | National Library of Medicine | World Journal of Surgical Oncology.
Answer: B. ERCP.
The next management task is to diagnose and stage the tumor accurately so that surgical treatment can be planned. ERCP is the single most useful endoscopic study for diagnosing ampullary carcinoma because it permits identification of the tumor, biopsy, and decompression.[38] In a prospective multicenter trial that included 30 patients with ampullary carcinoma, the sensitivities of several diagnostic studies in making a conclusive diagnosis were as follows[39,40]:
Although EUS is as sensitive as ERCP and more sensitive than CT and transabdominal US for detecting small ampullary tumors, it typically is not required for diagnosis. The spatial resolution of CT is inadequate to determine the degree of local tumor invasion.[38] The CT scan in the slide shows a hypervascular (suspected malignant) tumor at the papilla of Vater.
Image courtesy of World Journal of Surgical Oncology.
In the slide, MRI shows an ampullary tumor as a defect from the papilla of Vater to the lower CBD. Which of the following is not a common potential complication of ampullary carcinoma?
Image courtesy of World Journal of Surgical Oncology.
Answer: F. All of the above are potential complications.
Answers A through E are all common potential complications of ampullary carcinoma.[34] In the image on the left of the slide, ERCP yields findings similar to those of MRI in slide 32. In the image on the right, intraductal US reveals a torose lesion (dotted arrow) at the lower CBD.
Image courtesy of World Journal of Surgical Oncology.
The prognosis for patients with ampullary carcinoma depends on accurate staging and appropriate surgical treatment. Like GBC and CCC, cancer of the ampulla of Vater is staged according to the TNM system of the AJCC and the UICC. The importance of pancreatic invasion and lymph node metastasis is emphasized.[9,15]
Table adapted from AJCC Staging Manual, 7th ed.[15]
The image in the slide shows a transected pancreas at the pancreatic neck. A periampullary malignancy is visible.
A 60-year-old woman presents with fluctuant jaundice, weight loss, and pancreatitis. Endoscopy demonstrates a tumor protruding from the ampulla of Vater.
Which of the following is the preferred treatment in this scenario?
Image courtesy of Medscape.
Answer: B. Pancreaticoduodenectomy (Whipple procedure).
Pancreaticoduodenectomy is the standard approach for ampullary cancer. Surgical outcomes from pancreaticoduodenectomy for ampullary cancer have been improving, and reported mortality figures from this operation are decreasing. Over the past decade, average 5-year survival rates have been higher than 35%. In contemporary single-institution series, rates of potentially curative resection have increased from approximately 80% to more than 90%.[41] The image in the slide depicts an ulcerated growth in the ampulla of Vater in a pancreaticoduodenectomy specimen.
Image courtesy of Journal of the Pancreas.
The image in the slide shows protrusion of the ampulla of Vater into the duodenum.
Which of the following is not a contraindication for surgical resection of an ampullary cancer?
Image courtesy of Wikimedia Commons.
Answer: D. Ampullary malignancy larger than 1 cm.
Answers A, B, C, and E are all contraindications to surgical resection.[34] However, pancreaticoduodenectomy is the preferred treatment for ampullary malignancies greater than 1 cm in size. The image in the slide shows the process of kocherization, which is performed to assess the resectability of the tumor.
Image from Alila07 | Dreamstime.
The image in the side shows a pancreaticoduodenectomy (Whipple procedure). Local resection is not an acceptable alternative to pancreaticoduodenectomy for ampullary tumors, because recurrence is too common and unpredictable.[42] An overall survival advantage has been reported in patients receiving adjuvant chemoradiation therapy. Chemotherapeutic agents may be useful in the progressive disease state for the alleviation of symptoms postoperatively.[43] For patients with unresectable ampullary tumors, palliative surgery is the treatment of choice. Clinical outcomes include the alleviation of biliary and duodenal obstruction or pain. Either cholecystojejunostomy or hepaticojejunostomy bypass is performed.[44]
Image from Alila07 | Dreamstime.
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