Clinical findings among 62 Thais with cholangiocarcinoma
Cholangiocarcinoma, a malignancy of the biliary duct system, tends to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes and leading to biliary tract obstruction. In a retrospective case review, 62 cases diagnosed with cholangiocarcinoma between January 1997 and December 2001 at the King Chulalongkorn Memorial Hospital in Bangkok were studied. The most commonly observed clinical symptoms and signs were fever (96.8%), abdominal pain (87.1%) and malaise or weakness (83.9%). Fifty-one of the 62 tumours detected were distal extrahepatic (82.3%), seven perihilar (11.3%) and four intrahepatic (6.7%). There was a significant increase in serum bilirubin and marked elevation of serum alkaline phosphatase. Almost half (45.2%) of the patients presented with other pathological conditions, mostly cholangitis (19 cases) resulting from acute biliary tract obstruction and ascites (13 cases). The pathogens detected were similar in cases of cholangitis alone and cholangiocarcinoma. The major risk factor for this cancer in Thailand is believed to be exposure to liver fluke in insufficiently cooked traditional foods. As it is still endemic in Thailand, continuous prevention and surveillance of this public health problem are necessary.
Cholangiocarcinoma is the malignancy of the biliary duct system, originating in the liver and terminating at the ampulla of Vater. It is a tumour that arises from the intrahepatic or extrahepatic biliary epithelium. The aetiology of most bile duct cancers remains undetermined. It has been suggested that long-standing inflammation, as with primary sclerosing cholangitis or chronic parasitic infection, could play a role by inducing hyperplasia, cellular proliferation, and, ultimately, malignant transformation (Torok & Gores 2001). This carcinoma tends to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes and leading to biliary tract obstruction. Local extension into the liver, porta hepatis, and regional lymph nodes of the celiac and pancreatic–duodenal chains also occur. Resection offers the only chance of cure and long-term survival (Franco & Usatoff 2001).
Cholangiocarcinoma is a common cancer among South-east Asians, with the world's highest prevalence in north-eastern Thailand and Laos (Kullavanijaya et al. 1999; Wiwanitkit 2000). The custom of ingesting uncooked fish infected with liver fluke is believed to be the major risk factor for developing cholangiocarcinoma among the population. This short communication describes the clinical presentation of Thai patients with cholangiocarcinoma in a large Thai Red Cross Society hospital.
Materials and methods
The medical records of 62 patients diagnosed with cholangiocarcinoma between January 1997 and December 2001 at the King Chulalongkorn Memorial Hospital in Bangkok were retrospectively reviewed. In each case, the diagnosis had been made from the final histopathological results. Data collated from the records included the sex and age of each patient, the laboratory data collected during their hospitalization and location of the tumour.
In the 5-year admission period investigated, 62 patients were diagnosed with cholangiocarcinoma were studied. At presentation, all 62 cases – 35 men and 27 women – had a mean (SD) age of 56.81 years (10.88) (range: 32–86 years), most were suffering from fever (96.8%), abdominal pain (87.1%), and/or malaise and weakness (83.9%; Table 1) and all but one were HIV-negative. Twenty-one patients (33.9%) died in hospital.
Table 1. Clinical manifestations in the 62 patients with cholangiocarcinoma
|Abdominal pain||54 (87.1)|
|Malaise and weakness||52 (83.9)|
|Weight loss||37 (59.7)|
|Abdominal tenderness||27 (43.5)|
|Pale stool||19 (30.6)|
|Abdominal distension||13 (21.0)|
|Dark urine||3 (4.8)|
Fifty-one (82.3%) of the tumours detected were distal extrahepatic (82.3%), seven perihilar (11.3%) and four intrahepatic (6.7%). Three of the four intrahepatic tumours were restricted to the left lobe of the liver, one to the right lobe. All tumours could be seen as ill-defined biliary tract masses with obstruction on presurgical hepatic US and/or CT scans. Only 14 (22.6%) of the 62 tumours could be surgically removed.
On admission, the average white blood count, serum albumin, partial prothrobin time, serum aspartate transaminase, serum alanine transaminase, serum alkaline phosphatase (ALP) and serum bilirubin were 7.34 ± 5.24 × 1000 WBC/mm3, 2.06 ± 0.42 g/dl, 39.42 ± 4.8 s, 78.17 ± 172.19 U/l, 132.33 ± 96.11 U/l, 839.53 ± 844.27 U/l and 14.10 ± 11.47 g/dl, respectively. Stool examinations were performed in 35 cases and revealed no Opisthorchis viverrini.
In 28 (45.2%) of the 62 cases, other associated pathological conditions were identified during admission, mostly cholangitis (19 cases) and ascites (13 cases) (Table 2). Bile from all 19 cholangitis cases was cultured; all tested positive, each for only one pathogen. Escherichia coli was the most common (10 of 19; Table 3).
Table 2. Associated pathological conditions in the 28 patients with cholangiocarcinoma
|Acute cholangitis||19 (67.9)|
|Pleural effusion||3 (10.7)|
|Renal failure||2 (7.1)|
|Hepatic failure||2 (7.1)|
|Hepatic fistula||1 (3.6)|
|Hypoglycemic shock||1 (3.6)|
Table 3. Pathogens isolated from the 19 cholangitis cases
|Escherichia coli||10 (52. 6)|
|Pseudomonas aeruginosa||5 (26.3)|
|Enterobacter cloacae||2 (10.5)|
|Enterococcus fecalis||1 (5.3)|
|Acinetobacter buamannii||1 (5.3)|
According to our study, cholangiocarcinoma affects both sexes, and most cases are middle-aged patients. Males (56.5%) are affected slightly more often. The incidence was approximately 62 of 100 000 admission cases during the study period. Many findings in our study differed from Western studies, where the incidence was less than five of 100 000 (Johnson et al. 2001; Torok & Gores 2001; Weber et al. 2001). The average age of our cases was younger, and the incidence significantly higher, reflecting the fact that cholangiocarcinoma is an important public health problem and confirming that Thailand is the endemic area with the world's highest incidence (Kullavanijaya et al. 1999).
Although this malignant tumour of the bile duct is usually slow-growing and late to produce obstruction or spread, all of our cases presented with the biliary tract obstruction. Unfortunately, by the time diagnoses were made, the tumours were usually too advanced to remove surgically. Interestingly, we found no case of primary sclerosing cholangitis as the baseline chronic inflammation relating to the tumour. Indeed opisthorchiasis together with nitrosamine exposure because of traditional eating habits is believed to be the major risk factor in Thailand (Srivatanakul et al. 1991).
Most of the tumours in our study are defined as distal extrahepatic lesions. This finding is different from the reports from the West, which the perihilar lesion is the most common type (Torok & Gores 2001). Cholangiocarcinomas in Westerners are usually associated with primary sclerosing cholangitis (Torok & Gores 2001) while cholangiocarcinomas in Thais are usually associated with parasitic infestation (Schwartz 1980; Srivatanakul et al. 1991).
The clinical symptoms and signs observed in Thai patients with cholangiocarcinomas (Table 1) were similar to those described in the literature (Torok & Gores 2001). However, the three most common findings – abdominal pain, fever and chills, and abdominal tenderness – are not specific symptoms, which cannot lead to presumptive diagnosis. Some patients (21%) presented with inoperable abdominal distension by ascites (21%). Hence the early mortality in our study is higher in previous reports (Weber et al. 2001). A public information campaign about the aetiology and symptoms of this disease is needed in Thailand (Kullavanijaya et al. 1999).
In the laboratory investigations, a significant increase of serum bilirubin and marked elevation of serum ALP were observed, both hallmark laboratory findings for cholangiocarcinoma. According to a recent study, cholangiocarcinoma is the most common cause of hyperalkalinephosphatasaemia among Thai hospitalized patients (Wiwanitkit 2001). Unfortunately, high serum bilirubin and ALP levels are not specific for diagnosis of cholangiocarcinoma, whereas the determination of ALP isoenzymes seems more useful (Paritpokee et al. 1999).
Remarkably, although most of the cholangiocarcinoma in Thai patients relates to opisthorchiasis (Phuapradit et al. 1985; Kurathong et al. 2001), we did not find parasite eggs in any of the 35 patients who underwent stool examinations. A possible explanation is that these patients had severe biliary tract obstruction, inhibiting the passing of Opisthorchis eggs into the intestine (Kullakamthorn 1991). Hence stool examinations to detect the parasite are not useful in such advanced cases (Kullakamthorn 1991).
Almost half (45.2%) of our subjects had concomitant pathological conditions such as acute cholangitis resulting from biliary tract obstruction (Nauta 1989). The pathogens of the acute cholangitis were similar to those of cholangitis patients without cholangiocarcinoma (Leung et al. 2001; Sheen-Chen et al. 2000). Other rare conditions that occurred, e.g. hepatic fistula and hypoglycaemic coma, can be classified as complications of cholangiocarcinoma and confirm that most of our cases were patients with advanced disease.
In conclusion, most Thai patients with cholangiocarcinoma present with advanced disease and the outcome is usually fatal. There are differences in the disease pattern specific to Thailand: patients are younger, the incidence is much higher than in Western countries; the most frequent cause is exposure to the liver fluke in insufficiently cooked traditional foods (Srivatanakul et al. 1991), the lesions are largely extrahepatic. As this cancer is still endemic in Thailand, continuous prevention and surveillance of this public health problem is necessary (Kullavanijaya et al. 1999).
I am grateful to the Division of Medical Statistics, King Chulalongkorn Memorial Hospital, for collecting the case files. Arpha Pinyosophon and Siam Arayasantipart helped with the analysis of the data.
Dr Viroj Wiwanitkit, Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand. E-mail: firstname.lastname@example.org