Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - New Medicine 2/2004, s. 26-33
Dimitrous G. Panoussopoulos MD, PhD, S.D. Panoussopoulos MD
Bile duct cancer
Propaedeutic Surgery Clinic, Medical University of Athens, Athens, Greece
Bile duct cancer is a rare malignancy occuring in a biliary tree. Although the rate of occurence is low it is still worthy to be disscussed. Cholangiocarcinoma is a diagnosis in only 5 to 10% of all periampullary tumors. Diagnosis, staging, classification and and prognostic factors are presented.
Authors describe two kinds of treatment: surgical treatment and palliative therapy pointing out objectives, criteria and clinical outcomes of each. Adjuvant therapy seems to be no effective for cholangiocarcinoma.
Bile duct cancer represents a rare malignancy that can occur anywhere along the intrahepatic or extrahepatic biliary tree. It comprises less than 2% of all cancer diagnoses (1). The overall rate of occurrence is 1.2/100,000 people, with 2/3 of all cases developing in patients over 65 years of age (2). Over 95% are epithelial adenocarcinomas, also known as "cholangiocarcinomas”, predominating in the extrahepatic biliary tree. Men are affected slightly more than women and usually later in life (3). Most classification systems have separated intrahepatic from extrahepatic tumors and the latter have been traditionally subdivided into 3 groups, based on anatomical location (4). Upper third or hilar tumors are those located in the common hepatic duct and/or the right and left hepatic ducts including their confluence. Middle third tumors develop in the region between the upper border of the duodenum and extend to the common bile duct. Lower third or distal tumors arise between the anpulla of Vater and the upper border of the duodenum (4). Intrahepatic cholangiocarcinoma are rare neoplasms, comprising 6 to 10% of all cholangiocarcinomas, and they typically present as solitary hepatic masses (5). Tumors at the biliary confluence at the hilum of the liver (so-called Klatskin tumors) are the most frequently encountered and hilar cholangiocarcinomas (HCCA) comprise approximately 60% of the total (6). Middle and distal third tumors comprise about 20% each of all cholangiocarcinomas (6). Cholangiocarcinoma is also the diagnosis in only 5 to 10% of all periampullary tumors with ampullary, duodenal and pancreatic cancers being the rest of them. A small percentage of patients (<10%) may present with diffuse tumors of the entire extrahepatic bile duct and in such cases, surgery is never curative and prognosis is very poor (7). According to many authorities, the spectrum of extrahepatic cholangiocarcinomas is best classified into two broad groups: hilar or perihilar (HCCA) and distal (4). This is due to the fact that middle third lesions are relatively rare and are usually managed either as a proximal lesion with hilar resection or as a distal lesion with pancreatoduodenectomy. The classification to HCCA and total bile duct carcinoma correlates better with anatomic distribution and implies preferred treatment strategies: supraduodenal bile duct excision, portal lymphadenectomy, cholocystectomy, bilioenteric reconstruction and, in many cases, partial hepatectomy for HCCA and pancreaticoduodenectomy, or local bile duct excision for total cholangiocarcinomas (4).
Painless jaundice occurs in 90% of patients. Additional symptoms may be weight loss (30%), abdominal pain (20%), fever (10%) (8). Itching is the most commonly reported symptom occurring in up to 30% of patients and may precede the development of jaundice. Jaundice may be absent in the case of an intrahepatic cholangiocarcinoma or an HCCA that involves only the right or left hepatic duct. If the tumor spreads towards the portal vein, ipsilateral lobar atrophy can develop, in which case an isolated alkaline phosphatace elevation may be the only clinical finding.
Physical examination might reveal a moderate liver enlargement. The gallbladder can be palpable in distal tumors (Courvoisier´s sign). Ascites is rare. Advanced tumors obstructing the portal vein can lead to portal hypertension and splenomegaly (3).
Although cholangitis is a rare initial presentation, the rate of both its occurrence and that of bactobilia increases significantly with either endoscopic or percutaneous biliary tract instrumentation. The usefulness of stents in the asymptomatic jaundice patient is controversial. A two-fold increase in postoperative infections complications have been associated with preoperative stenting (9). Increased morbidity has been associated with preoperative biliary stenting in patients undergoing either biliary duct excisions or pancreaticoduodenectomy for cholangiocarcinomas (10, 11, 12). On the other hand, several authors have reported the usefulness of biliary stenting, which may provide several advantages such as normalization of coagulation function, reduction of circulating endotoxins, improvement of renal and immune function, and the most important one – facilitate the intraoperative identification of the right and left hepatic ducts at the case of the liver (3, 13).
Certain pathological conditions related to acute or chronic biliary epithelial injury appear to predispose to the development of cholangiocarcinomas 40% of autopsy specimens and 10% to 30% of liver explants after their transplantation from patients with primary sclerosing cholangitis (PSC) contained occult foci of cholangiocarcinoma (14). It seems, that PSC and cholangiocarcinoma may represent a spectrum of the same disease process. Another group of patients carrying an increased risk for cholangiocarcinoma are those with cystic disease of the biliary system in the form of choledochal cysts or Caroli´s disease, due to a chronic biliary inflammation associated with those conditions (7). Biliary tract infection with parasites endemic to Southeastern Asia, such as Clonorchis sinensis and Opisthorchis viverrin, chronic cholelithiasis, hepatolithiasis and previous cholecystectomy are also accounted among the risk factors for the development of these neoplasms (8). Chronic typhoid carriers and exposure to asbestos, thorium dioxide and nistrosamines are less well-documented risk factors (8).
Based on its macroscopic appearance, cholangiocarcinoma is subclassified into the following types: a.the papillary variant (about 10%), which has a tendency for multicentricity, is most common in the mid to distal bile duct and carries a more favorable prognosis, b.the nodular variant, which occurs most commonly in the upper and mid bile duct and usually presents as a fibrotic mass, c.the selerosing variant (about 70%), mainly encountered at the hilum and appears as an annular thickening of the duct wall with both longitudinal and radial tumor infiltrations, d. the rare diffuse variant presents with extensive involvement of the entire extrahepatic bile duct, e.the rare carcinoid tumors, and f.the tumors that metastatically involve the biliary tree, originating usually from colorectal cancers.
Hematogenous spread of HCCA is rare, while lymph node metastasis may be present up to 1/3 of the cases (15). Extensive subepithelial tumor spread beyond the gross tumor margin is also common and longitudinal spread may extend 15 mm to 20 mm proximally and 5 mm to 10 mm distally (16).
The objectives of preoperative evaluation of a patient with suspected cholangiocarcinoma are as follows: a.assessment of the extent of biliary tract and portal vein, b.assessment of liver function and status (lobular atrophy, concommitent liver pathology), c.evaluation of nodal and/or distant metastasis, and d.assessment of patient´s general status and tolerability for an operation.
Investigative radiology initially includes noninvasive studies such as U/S and CT, which are performed to generally assess the locoregional extent of tumor and the presence of metastases (3). U/S, especially when combined with duplex scanning, has an accuracy of over 50%. CT scans are also highly accurate at imaging small lesions and identifying their relationship to the portal triad and hepatic parenchyma. Delayed images after intravenously contrast-enhanced spiral CT scans are the most sensitive, since cholangiocarcinomas tend to return the contrast longer than adjacent normal tissue (3). In selected cases, a celiac and superior mesenteric arteriogram with late-phase portography may be useful to assess resectability, although not much utilized nowadays. Instead, when duplex U/S fails to reveal vascular involvement by tumor, operation is favored as the principal determinant of resectability (3). The efficacy of magnetic resonance cholangiopancreatography (MReP) has been already well documented and has largely replaced invasive methods (percutaneous and endoscopic cholangiography), especially among the advocates of limitation of preoperative biliary instrumentation (17).
Nevertheless, according to most authorities, cholangiography is mandatory when noninvasive studies suggest malignant biliary obstruction (3). Percutaneous transhepatic cholangiography (PTC) is the most useful and definitive radiologic test for bile duct cancer (3). It outlines the tumor and proximal biliary system and permits external drainage catheters placement above the lesion. Intraoperatively, these catheters assist in the identification of the proximal biliary tract and may be replaced by larger silastic transanastomotic stents if necessary (3). If resection or operative bypass are not possible, they can also be internalized to the duodenum or, less often, left to external drainage to alleviate the jaundice (3). ERCP, with or without endoscopic U/S, is best suited for distal biliary cancers and plastic stents may be left in place to relieve the obstruction (3).
Preoperative histological confirmation of a bile duct cancer might be difficult to obtain. Percutaneous needle biopsies and endoscopic brush biopsies have sensitivity of less than 50% and one can not rely on negative results (18). Histological confirmation is, thus, not mandatory before operative exploration. Differential diagnosis includes gallbladder cancer, metastatic disease, rare primary neoplasms (eg carcinoid), Mirrizzi´s syndrome, focal biliary sclerosis and other benign conditions. In the absence of clear evidence of unresectability, all suspected cholangiocarcinomas should be considered for resection (19).
At preoperative investigation, several criteria for unresectability have been established, which include:
– medical comorbidities limiting the patient´s ability to undergo major surgery,
– significant underlying liver disease prohibiting liver resection necessary for curative surgery,
– bilateral or multifocal intrahepatic disease on cholangiography that precludes resection,
– tumor extension to secondary biliary radicals (Bismuth´s types III, IV),
– tumor invasion of the main portal trunk,
– bilateral involvement of hepatic arterial or portal venous structures,
– lobar atrophy with contralateral portal vein involvement,
– contralateral tumor extension to secondary biliary radicals,
– evidence of metastases to N2 level lymph nodes (peripancreatic, paraduodenal, peripertal,
– celiac, superior mesenteric, posterior pancreaticoduodenal),
– presence of distant metastases.
Selection of patients who are "fit” to undergo radical surgery is sometimes different. Assessing liver function relies on standard laboratory tests of hepatic metabolic and synthetic function. B and C patients are not candidates for curative surgery if a liver resection is required. Cardiopulmonary evaluation includes pulmonary function tests (most important in smokers) and an EKG. A more invasive cardiac evaluation is indicated on patients with significant comorbidities or poor performance medical status.
Multiple staging systems have been proposed. The two most commonly used are the TNM system devised by the AJCC and the modified Bismuth-Corlette classification for HCCA (20, 21), (Tables 1, 2, Figure 1). However, in both systems potential hepatic artery or portal venous involvement by the tumor and the functional status of the liver are not taken into account. Actually, according to Memorial Sloan Kettering Hospital´s experience, portal vein involvement with tumor was the only independent predictor of respectability (22). As a result, Blumgart et al. proposed a modified T-staging system, which takes into consideration both vascular involvement by tumor extension and the presence of liver atrophy (22), (Table 3).
Table 1. AJCC staging systems for cholangiocarcinoma.
Stage 0TisN0M0
Stage IT1N0M0
Stage IIT2N0M0
Stage IIIT1,2N0M0
Stage IVAT3AnyM0
Stage IVBAnyAnyM1
AJCC, American Joint Committee on Cancer; Tis, carcinoma in situ; T1, tumor invades subepithelial connective tissue; T3, tumor invades adjacent structures, i.e., liver, pancreas, duodenum, stomach, gallbladder, colon, or stomach; N1, metastasis in the cystic duct, pericholedochal, and/or hilar lumph nodes; N2, metastasis in the peripancreatic (head only), paraduodenal, periportal, celiac, superior mesenteric, and/or posterior pancreaticoduedenal lymph nodes; M0, no distant metastases.
Table 2. Modified Bismuth-Corlette classification for hilar cholangiocarcinoma.
Type IBelow the confluence
Type IIConfined to confluence
Type IIIaExtension into right hepatic duct
Type IIIbExtension into left hepatic duct
Type IVExtension into right and left hepatic ducts
Other modifications of the Bismuth-Corlette classification system have been suggested but have not been widely accepted.
Fig. 1. Bismuth, Nakache and Diamond classification, for HCCA.
Table 3. Proposed modified T-stage criteria for hilar cholangiocarcinoma.
T1Tumor confined to the confluence and/or right or left hepatic duct without portal vein involvement or liver atrophy
T2Tumor confined to the confluence and/or right or left hepatic duct with ipsilateral liver atrophy; no portal vein involvement demonstrated
T3Tumor confined to the confluence and/or right or left hepatic duct with ipsilateral portal vein branch involvement with/without associated ipsilateral lobar liver atrophy; no main portal vein involvement (occlusion, invasion, or encasement)
T4Any of the following:
1) Tumor involving both right and left hepatic ducts up to secondary biliary radicals bilaterally
2) Main portal vein encasement

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