Article
Biliary Tract Cancer in Nepal
Introduction and Epidemiology
Cancer of the biliary tract can be divided into cancer of the bile ducts (cholangiocarcinoma) and cancer of the gall bladder. Cholangiocarcinoma, at a global level, is uncommon – less than 01% of global cancer falls into this category. However, it can be difficult to obtain precise figures, since in most cancer registries it is included with hepatocellular carcinoma, which arises from the liver cells themselves. Cholangiocarcinoma arises either from the bile ducts within the liver or the larger ducts outside the liver that transport bile to the intestine. Gall bladder cancer arises from the gall bladder and is generally more common than cholangiocarcinoma, but still, overall, a rare cancer. However, these diseases, both of which are predisposed to by infectious or inflammatory diseases of the biliary tract, have a high incidence in particular world regions. Cholangiocarcinoma, for example, is known to have a high incidence in parts of south and east Asia, where there is a strong association with infection by liver flukes (Opisthorchis viverrino in Thailand and West Malaya, and Clonorchis sinensis in China), which infect many millions of people in these regions due to the common habit of eating raw fish, which unfortunately, are often infected by these parasites. The population registry in Thailand (Khon Kaen) reports a particularly high incidence of cholangiocarcinoma which accounts for 85% of all liver cancer and is believed to be primarily related to Opisthorchis viverrino infection. In this registry liver cancer has an incidence of some 32 and 15 per 100,000 in males and females respectively (Globocan 2002). Infectious hepatitis of types B or C, strongly associated with hepatocellular carcinoma, appear to play a limited, if any role, in the epidemiology of biliary tract cancer. Congenital abnormalities of the biliary tract may be associated with both types of biliary tract cancer, probably because of the irritant properties of some of the constituents' bile, or even of diversion of pancreatic juices, containing digestive enzymes into the biliary tract. Chronic inflammatory diseases involving the biliary tract (sclerosing cholangitis) and bowel (ulcerative colitis) predispose to biliary tract cancer, especially cholangiocarcinoma1. Exposure to toxic chemicals may also predispose to cholangiocarcinoma, and smoking has been implicated in gall bladder cancer.
Gall bladder cancer is related in the majority of cases to prior inflammation of the gall bladder, nearly always associated with gall stones. It has a relatively high incidence in some populations and regions. In Northern India it is the commonest cancer of the gastro-intestinal tract in women (in whom it generally has a higher incidence, in contrast to cholangiocarcinoma, which has a higher incidence in men).2 Predisposing factors to gall bladder cancer include diet and genetic factors – the disease has a much higher incidence in native American and Hispanic populations in the south-western USA for example, all of whom have a high incidence of gall stones. In the Pima Indians in Arizona, 70% of women have gall stones by the age of 30 years. Many develop gall bladder cancer, and there is a very high incidence of obesity and diabetes. Gall bladder cancer is also associated with chronic typhoid infection of the gall bladder. Smoking and exposure to other hazardous chemicals may be risk factors in some populations.
Little is known of the risk factors that pertain to the apparently increased incidence of this disease in Nepal, although they are likely to be similar to those in northern India. The most common cause of both cancers is probably chronic infection, most probably, bacterial; liver flukes are not known to be prevalent in Nepal, nor is the custom of eating raw fish. Primary sclerosing cholangitis, choledochocal cyst and ulcerative colitis are also believed to be rare. Having no proper cancer registration system, it is difficult to know the exact incidence of either cholangiocarcinoma or gall bladder cancer and there is no evidence of higher prevalence in particular regions, or in specific ethnic groups or occupations, although there is some indication that patients come predominantly from lower socioeconomic backgrounds. Whereas both cancers occur generally in older individuals (above 60 years), the average age at presentation in Nepal tends to be lower.
Prevention
Prevention of cholangiocarcinoma is clearly possible in populations prone to infection by liver flukes and in northern India, while dietary modifications, such as emphasis on fruits and vegetables, may lead to a reduction in gall-bladder cancer. Removal of gall stones has been suggested to be of value in the prevention of gall bladder cancer, and clearly, if congenital biliary tract abnormalities are present, early surgical correction may avoid the later risk of cancer.
Presentation and Diagnosis
Both types of cancer of the biliary tract can present with similar features, since obstruction of the flow of bile is common, leading to jaundice and discomfort or pain in the right hypochondrium (the region below the right ribcage, where the liver and gall bladder are situated). The pain may be similar to that caused by gall stones, although tends to be more constant. Jaundice may be accompanied by severe itching, nausea and vomiting, and weight loss is common. A mass may be palpable in the right upper abdomen, either from distension of the gall bladder because its outflow is obstructed, or because of accumulation of tumor in this region. In advanced cases, ascites (fluid in the abdominal cavity) may occur, usually due to spread of disease to other parts of the abdomen or pelvis.
Before they come to hospital more then 80% of patients have been treated by traditional vaidas, quack (charlatans), faith healers, paramedics and even some non-specialist doctors. Jaundice in Nepal is always taken by patients to be caused by infectious hepatitis – by far the commonest cause and they are initially reluctant to go to hospital. Eventually, after at least several weeks or months have passed without improvement – and often with significant deterioration in spite of traditional medical treatments they may have received, they are finally referred to a specialist. Unfortunately, by then, their disease is usually too advanced to be cured, and complications such as ascites have often developed.
While liver function tests are available to all, imaging tests such as computed tomography (CT), magnetic resonance imaging and cholangiography are rarely available. Endoscopic retrograde cholangiopancreatography (ERCP) is and excellent means of demonstrating, by retrograde injection, the site of obstruction in the biliary tree while percutaneous transhepatic cholangiography (PTC), which enables the biliary tree proximal to the obstruction to be examined, but both are costly and beyond the reach of the bulk of the population. Ultrasound may be the most widely available and least expensive imaging tool, and in gall bladder cancer, it can identify a mass in most patients (perhaps 75%). It is also useful in detecting dilated bile ducts and the presence of metastases in the liver. The more sophisticated endoscopic ultrasound (EUS), which can be used to assess the degree of regional spread, is not generally available in Nepal. The tumor marker, carcinoembryonic antigen, is frequently abnormal in cholangiocarcinoma but has not been shown to be of value in gall bladder cancer. In both cancers, however, carbohydrate antigen 19-9 is frequently elevated. Alpha-fetoprotein is not elevated in biliary tract cancer, and provides a distinguishing feature from hepatocellular carcinoma. Promising new “molecular” markers, using proteomics on serum, are not available in Nepal. Preoperative histopathological diagnosis, using CT or ultrasound-guided needle biopsy, the standard diagnostic procedure, is not widely performed because of the limited availability of the necessary expertise and equipment. Most biliary tract cancers, whether of the gall bladder or bile ducts, are adenocarcinomas.
Staging
The extent of disease in biliary tract cancer, as in all cancers, is critical to outcome. The stage is determined by the usual criteria, i.e., size of the tumor and degree of local invasion (T), the extent of regional spread via lymph nodes (N) and the presence of distant metastases (M). Both types of biliary tract cancer are therefore amenable to the TNM system, which takes account of these features, and in which each element (T, N, or M) is given a numerical value, i.e., from T0 to T4, N0 to N1 or N2 (in gall bladder cancer and cholangiocarcinoma respectively) or M0 to M1 (i.e., present or absent) in the case of distant metastases. Patients with minimal local invasion, no nodes and no distant metastases are assigned to stage I, and patients with distant metastases to stage IV. Stages II and III and their subcategories include various degrees of tumor invasion with or without regional lymph node spread that differ somewhat with each disease. In Nepal, nearly all patients have stage III or IV disease at the time of diagnosis.
Treatment
Biliary tract cancer is curable only when the extent of disease is sufficiently limited as to permit complete surgical resection. Unfortunately, this is possible in perhaps no more than 10-15% of cases anywhere in the world, such that surgery is primarily palliative in intent. However, in rare cases of gall bladder cancer with stage T1N0M0 disease, a simple cholecystectomy may be curative. Less than 25% of the cases of biliary tract cancer in Nepal are operated on, even for palliation. The primary objective in these cases is to relieve biliary obstruction, either through surgical bypass or to insert a “T tube” into the biliary tract for external biliary drainage. T-tube insertion is the most frequently performed procedure. Relief of biliary obstruction by internal stenting is not available in the public sector, being a costly procedure. Neither radiation therapy nor chemotherapy are standard components of treatment anywhere in the world, although in some patients radiation therapy may be used to reduce the size of the tumor (in rare cases, to the point of surgical resectability). Few patients in Nepal are candidates for radiatiotherapy, which, in any event, is available only in four centers in the entire country. Chemotherapy also has a limited role in biliary tract cancer, although 5-FU or regimens including this drug, in which responses may be seen in up to 25% of patients with gall bladder cancer, may be recommended in high-income countries either after surgery or in a palliative setting. A role for chemotherapy in cholangiocarcinoma has not been established.
Treatment Outcome
Survival rates in patients with surgically resectable disease are very good, but since few patients fall into this category, survival rates are very low everywhere in the world. In Nepal, almost all patients die, and unfortunately, few even have adequate palliative therapy. Once a patient knows that the disease is incurable he or she is generally reluctant to return to hospital or even to go to a hospice (if available) for terminal care. This applies to many other cancers, and is likely to be ameliorated only by an expansion of home palliative care services which are presently extremely limited. This also means that assessment of the morbidity and mortality of biliary tract cancer is difficult at best, but it is probable that few patients survive for longer than six months.
Manohar Lal Shrestha
Nepal Medical College and Teaching Hospital Atterkhel
Kathmandu, Nepal
References
1. Parkin DM, Ohshima H, Srivatanakul P, Vatanasapt V. Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev. 1993;2:537-44.
2. Kapoor VK, McMichael AJ. Gallbladder cancer: an ‘Indian’ disease. Natl Med J India. 2003; 16:209-13.
