Zografos GN, Farfaras A, Zagouri F, Chrysikos D, Karaliotas K (2011) Cholangiocarcinoma: principles and current trends. Hepatobiliary Pancreat Dis Int, 10(1):10-20
Abstract: Surgical treatment involves major resections of the liver, pancreas and bile duct, with considerable mortality and morbidity
Introduction
CCA is relatively uncommon with an annual incidence of 1-2 cases per 100 000 in the Western countries. However, rates have been rising worldwide over the past decades, partly due to advances in diagnostic techniques.[2, 3]
The peak age for CCA is the seventh decade, with a slightly higher incidence in men. Despite its significant increase, the incidence of the disease remains low, with marked global variations. The highest rates are reported in northeast Asia where the disease affects 96 per 100 000 men. At about 100 times greater than that in the West, this rate presumably reflects differences in local risk factors and genetics. Despite its low incidence, CCA is responsible for about 13% of primary liver cancers and accounts for 1.3% to 2.6% of annual cancer-related deaths worldwide.[4] Most patients who undergo resection die of local tumor recurrence.[6] This is related to the fact that complete surgical resection with tumor-free histological margins is difficult to perform. It is seen only between 10% and 50% of resected specimens.[7]
Risk Factors
The most common predisposing factor for CCA is primary sclerosing cholangitis (PSC), which has been reported in up to 40% of patients suffering from a specific malignancy. Although it has been shown that the risk of development of CCA is higher within the first 2.5 years following diagnosis of PSC, no association has yet been established between the duration of PSC and the incidence of CCA.[4-8] In addition, patients with intrahepatic biliary stones have a 10% risk of developing CCA, while up to 70% of patients with histologically confirmed CCA have hepatolithiasis.[9-12] Moreover, biliary malformations such as Caroli's disease and congenital fibropolycystic disease carry a 10% to 15% risk of malignancy.[13] Liver fluke infection is another important risk factor for the development of CCA. Infection by Opisthorchis viverrini has been demonstrated as a definite cause of human CCA, whereas infection by Clonorchis sinensis has been linked to a higher incidence of CCA.[14, 15] Chronic pancreatitis, non-specific liver cirrhosis, history of biliary-enteric drainage for benign disease, exposure to environmental toxins, primarily including dioxins, increased body mass index and consumption of alcohol have also been associated with a higher prevalence of CCA.[16, 17] Moreover, many hormones, neuropeptides, and neurotransmitters have been found to regulate malignant and non- malignant cholangiocyte pathways in patients with chronic biliary diseases.[18]
Hepatitis B (HBV) and hepatitis C (HCV) are established risk factors for hepatocellular carcinoma and their roles have been proposed in the development of CCA. Various studies have demonstrated a statistically significant increase of antibodies against HBV among CCA patients, while up to 30% of them have antibodies against HCV.[19, 20]
Symptoms: Differential Diagnosis
Jaundice is the most common manifestation of bile duct cancer.Jaundice often occurs later in perihilar or intrahepatic tumors and is a marker of advanced disease. Abdominal pain is relatively common in advanced disease and is often described as a dull ache in the right upper quadrant.
Preoperative evaluation
ERCP, DIA, FISH
Surgery
Surgery is the treatment of choice as it is the only potentially curative therapy for patients suffering from CCA.
The resectability of CCA depends on the exclusion of peritoneal and distant lymph node metastases and the absence of major vascular invasion.[36] Exclusion criteria for resection include encasement of the contralateral portal vein or hepatic artery, contralateral involvement of secondary biliary radicles and lymph node metastases beyond the hepatoduodenal ligament. Peritoneal metastases that are overlooked on abdominal CT should be excluded laparoscopically.[37]
Segmentectomy or lobectomy is the preferred operation for solitary intrahepatic CCAs.[38] despite the improvement achieved over the last decade, the5-year survival rates still range from 13% to 44%.[5, 42-44]
Is there a role for Liver transplantation?
Transplantation for intrahepatic or extrahepatic tumors is fraught with high recurrence rates and rapid metastases of the tumor (peritoneal spread, or distant metastases). For this reason, it has been abandoned. 71] Extrahepatic nodal disease or metastases are also contraindications to liver transplantation. In addition, recent multicenter series have reported unsatisfactory results with 3-year survival rates of less than 30% and a 26-month median time to recurrence.[72-74]
Palliative Treatment
Photodynamic therapy (PDT) has been used in palliative management with encouraging results. It is a minimally invasive procedure and is based on photosensitizers that are chemical compounds stimulated by light of a specific wavelength. A photosensitizer is administered to the patient and the tissue to be treated is exposed to light suitable for stimulating the photosensitizer. The close proximity of the photosensitizer and an oxygen molecule creates a stimulated singlet state oxygen molecule, which induces tumor cell death through apoptosis or necrosis, occlusion and thrombosis of small vessels supporting the malignant tumor.[85-87]
Despite the use of PDT providing such promising data, its evaluation as an adjuvant treatment remains uncontrolled and therefore should only be regarded as palliative management.
Neo adjuvant Therapy
The CCA cell response to radiation is so poor that radiation therapy has been abandoned in most centers. Moreover, this procedure has been associated with a marked deterioration in patients' quality of life and significant morbidity, including gastrointestinal bleeding, biliary strictures, intestinal obstruction, and hepatic decompensation.[98-100]
In summary, chemotherapy, radiation and PDT cannot be unconditionally recommended for adjuvant therapy of CCA.
Prognostic Factors
Among numerous prognostic factors that have been described, the most important for long-term survival are negative surgical margins, lymph node status, and differentiation grade of the tumor. Non-free margins are associated with a major decrease in survival rates and an increase in recurrence rates.[102-107]
A 5-year survival rate of 14% for patients with regional LN metastases and of 12% for those with positive para-aortic nodes has been reported. LN micrometastasis has no impact on survival in patients with otherwise negative LNs.[107-110]
Portal vein invasion is a strong prognostic factor of CCA and the actual number of 5-year survivors is limited, reaching only 9.9% compared with patients without portal vein resection (36.8%).[54]
Abstract: Surgical treatment involves major resections of the liver, pancreas and bile duct, with considerable mortality and morbidity
Introduction
CCA is relatively uncommon with an annual incidence of 1-2 cases per 100 000 in the Western countries. However, rates have been rising worldwide over the past decades, partly due to advances in diagnostic techniques.[2, 3]
The peak age for CCA is the seventh decade, with a slightly higher incidence in men. Despite its significant increase, the incidence of the disease remains low, with marked global variations. The highest rates are reported in northeast Asia where the disease affects 96 per 100 000 men. At about 100 times greater than that in the West, this rate presumably reflects differences in local risk factors and genetics. Despite its low incidence, CCA is responsible for about 13% of primary liver cancers and accounts for 1.3% to 2.6% of annual cancer-related deaths worldwide.[4] Most patients who undergo resection die of local tumor recurrence.[6] This is related to the fact that complete surgical resection with tumor-free histological margins is difficult to perform. It is seen only between 10% and 50% of resected specimens.[7]
Risk Factors
The most common predisposing factor for CCA is primary sclerosing cholangitis (PSC), which has been reported in up to 40% of patients suffering from a specific malignancy. Although it has been shown that the risk of development of CCA is higher within the first 2.5 years following diagnosis of PSC, no association has yet been established between the duration of PSC and the incidence of CCA.[4-8] In addition, patients with intrahepatic biliary stones have a 10% risk of developing CCA, while up to 70% of patients with histologically confirmed CCA have hepatolithiasis.[9-12] Moreover, biliary malformations such as Caroli's disease and congenital fibropolycystic disease carry a 10% to 15% risk of malignancy.[13] Liver fluke infection is another important risk factor for the development of CCA. Infection by Opisthorchis viverrini has been demonstrated as a definite cause of human CCA, whereas infection by Clonorchis sinensis has been linked to a higher incidence of CCA.[14, 15] Chronic pancreatitis, non-specific liver cirrhosis, history of biliary-enteric drainage for benign disease, exposure to environmental toxins, primarily including dioxins, increased body mass index and consumption of alcohol have also been associated with a higher prevalence of CCA.[16, 17] Moreover, many hormones, neuropeptides, and neurotransmitters have been found to regulate malignant and non- malignant cholangiocyte pathways in patients with chronic biliary diseases.[18]
Hepatitis B (HBV) and hepatitis C (HCV) are established risk factors for hepatocellular carcinoma and their roles have been proposed in the development of CCA. Various studies have demonstrated a statistically significant increase of antibodies against HBV among CCA patients, while up to 30% of them have antibodies against HCV.[19, 20]
Symptoms: Differential Diagnosis
Jaundice is the most common manifestation of bile duct cancer.Jaundice often occurs later in perihilar or intrahepatic tumors and is a marker of advanced disease. Abdominal pain is relatively common in advanced disease and is often described as a dull ache in the right upper quadrant.
Preoperative evaluation
ERCP, DIA, FISH
Surgery
Surgery is the treatment of choice as it is the only potentially curative therapy for patients suffering from CCA.
The resectability of CCA depends on the exclusion of peritoneal and distant lymph node metastases and the absence of major vascular invasion.[36] Exclusion criteria for resection include encasement of the contralateral portal vein or hepatic artery, contralateral involvement of secondary biliary radicles and lymph node metastases beyond the hepatoduodenal ligament. Peritoneal metastases that are overlooked on abdominal CT should be excluded laparoscopically.[37]
Segmentectomy or lobectomy is the preferred operation for solitary intrahepatic CCAs.[38] despite the improvement achieved over the last decade, the5-year survival rates still range from 13% to 44%.[5, 42-44]
Is there a role for Liver transplantation?
Transplantation for intrahepatic or extrahepatic tumors is fraught with high recurrence rates and rapid metastases of the tumor (peritoneal spread, or distant metastases). For this reason, it has been abandoned. 71] Extrahepatic nodal disease or metastases are also contraindications to liver transplantation. In addition, recent multicenter series have reported unsatisfactory results with 3-year survival rates of less than 30% and a 26-month median time to recurrence.[72-74]
Palliative Treatment
Photodynamic therapy (PDT) has been used in palliative management with encouraging results. It is a minimally invasive procedure and is based on photosensitizers that are chemical compounds stimulated by light of a specific wavelength. A photosensitizer is administered to the patient and the tissue to be treated is exposed to light suitable for stimulating the photosensitizer. The close proximity of the photosensitizer and an oxygen molecule creates a stimulated singlet state oxygen molecule, which induces tumor cell death through apoptosis or necrosis, occlusion and thrombosis of small vessels supporting the malignant tumor.[85-87]
Despite the use of PDT providing such promising data, its evaluation as an adjuvant treatment remains uncontrolled and therefore should only be regarded as palliative management.
Neo adjuvant Therapy
The CCA cell response to radiation is so poor that radiation therapy has been abandoned in most centers. Moreover, this procedure has been associated with a marked deterioration in patients' quality of life and significant morbidity, including gastrointestinal bleeding, biliary strictures, intestinal obstruction, and hepatic decompensation.[98-100]
In summary, chemotherapy, radiation and PDT cannot be unconditionally recommended for adjuvant therapy of CCA.
Prognostic Factors
Among numerous prognostic factors that have been described, the most important for long-term survival are negative surgical margins, lymph node status, and differentiation grade of the tumor. Non-free margins are associated with a major decrease in survival rates and an increase in recurrence rates.[102-107]
A 5-year survival rate of 14% for patients with regional LN metastases and of 12% for those with positive para-aortic nodes has been reported. LN micrometastasis has no impact on survival in patients with otherwise negative LNs.[107-110]
Portal vein invasion is a strong prognostic factor of CCA and the actual number of 5-year survivors is limited, reaching only 9.9% compared with patients without portal vein resection (36.8%).[54]
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