Cholangiocarcinorna : A decade ' s experience at a comm uni ty-- based university hospital

Two young patients with cholangiocarcinoma associated with salmonella carriage and ulcerative colitis, respectively, were seen at a community-based university hospital. This experience prompted a review of all cases with this tumour seen in the past decade. Twenty-seven patients were found. Their clinical, laboratory, and histological features, and therapeutic outcome are described. Of the group, only 7.4% were younger than 30 years of age and 14.8% had recognized associated conditions. The most common definable tumour was a we': differentiated hilar cholangiocarcinoma. Overall outcome was poor (six months). Survival was similar in patients undergoing palliative stents or surgery. In a small subgroup of surgically treated patients who received either radiotherapy or postoperative drainage, survival seemed to be better. Can J Gastroenterol 1990;4(2):65-69

C HOLANGIOCARCINOMA IS THE second most common malignancy after primary hepatocellular carcinoma that affects the liver and biliary system. Surgical experience with such a neoplasm is limited, although the literature is relatively extensive on the subject. Treatment of this malignancy remains poor, despite the general trend towards a more aggressive surgical approach. A greater clinical awareness coupled with the newer investigative modalities for the biliary tract might conceivably find earlier lesions that are amenable to surgery and improve the dismal prognosis.
Clinical experience with two young men who developed cholangiocarcinoma in association with salmonella carriage and inflammatory bowel disease prompted a review of the general experience with these neoplasms at a community-based university hospital over the previous decade. Presentation, associated illness, and management of these cases reflect the current experience in the literature.  Biochemistry showed a rotal bilirubin of 168 nmol/L with a 66% conjugated fraction. Alkaline phosphatase was 225 iu/L while the serum aspartate a minotransferase was 55 iu/L. The hemoglobin was 126 g/L, white count was 7.1 X 10 9 /L and coagulation studies were normal. Hepatitis B surface antigen test was negative.

PATIENTS AND METHODS
Subsequent stool cultures were positive for salmonella group C, and two ova of Ascaris lumbricoides were detected. Radiological investigation revealed a normal c hest x-ray. An abdominal ultrasound showed dilated intrahepatic ducts confined to the left lobe. An abdominal computerized tomography scan confirmed these findings. Retrograde c ho langiography could not better define the lesion. A bone scan and a barium meal were reported as normal.
The patient was taken ro the operating room, where a polypo id tumour of the distal common bile duct was localized. This lesion was found to extend to the hilum. Pathology confirmed a well differentiated, mucin-producing, papillary adenocarcinoma with regional lymph n ode metastases showing a desmoplastic reaction. Stains on histology for markers of hepatitis B were negative. The tumour was not resectable and a cholecystectomy and choledochojejunostomy/gastrojej unostomy with enteroenterostomy were carried our. C ul-cures of bile at the time of surgery also grew salmonella group C. No parasites were found.
The postoperative course was complicated by a febrile episode; however, urine and bloo<l c ultures were negative. H e was subsequently discharged and returned one month later to Indonesia.

CASE TWO
A 21-year-old immigrant from Romania presented after a seven week history of vague right upper quaclranr pain and mild weight loss. He had a six year history of poorly contro lled ulcerative colitis until one year prior to admission, when his symptoms improved on sulfasalazine. A barium enema and flexible sigmoidoscopy at that tune confirmed the diagnosis. Two weeks prior to admission, physical examination and abdominal ultrasound were normal.
However, biochemistry showed marked anicteric cholestasis. H e was subsequently admitted for work-up of this abnormality.
On physical examination, viral signs were normal. He was somewhat cachectic and the liver edge was now palpable 2 cm below the costal margin. Stools were negative for blood.
Biochemistry revealed an alkaline phosphatase of 116 iu/L, gammaglutamyl transpeptidase of 404 iu/L and bilirubin of 15 µmol/L. Hemoglobin was normal. Hepatitis B surface antigen was negative.
An hepatobiliary scintigraph revealed incomplete emptying of the right lobe. A liver-spleen scan showed hepatomegaly and a possible mass in the region of the porta hepatis. An abdominal computed tomography scan revealed an extensive hypodcnse area in the right lobe. H e refused endoscopic cholangiography.
At surgery, the entire right lobe of the liver was found to be replaced by tumour. There were numerous metastatic nodules to the peritoneum as well as lymph node masses at the root of the mesentery. Biopsies of the li ver, nodules and lymph nodes confirmed the presence of a well differentiated adenocarcinoma consistent with bile duct origin.
He made an uneventful recovery

HOSPITAL EXPERIENCE
Twenty-seven patients including the two index cases were collected from the decade under review. Their demographic featu res are shown in Figure l. Only two patients were younger than JO years old (the present cases).
Although most patients noted jaundice or pruritus, abdominal pain was not prominent initially. However, pain was exacerbated as the disease pro-gre~"J. Four patients presented with symptoms or findings other than those focused on the biliary tract. One of these patients presented with a migratory thrombophlebitis for two months prior to admission. Another patient presented with a chief complaint of progressive fatigue. Two patients presented with symptoms referred to the respiratory tract, progressive shortness of breath and hemoptysis. On physical examination, 19 patients had hepacomegaly or a mass and eight had normal findings. On biochemistry, all 27 patients exhibited features of cholestasis. The majority were anemic and one- A search for associated conditions in this group of patients revealed 10 with such features (Table I). In addition to salmonella infection and inflammatory bowel disease, one patient had a previously resected choledochal cyst. A 65-year-old woman had both salmonellosis in the past and a bronchogenic carcinoma surgically treated 11 years earlier. A 74-year-old woman had concomitant linitis plastica which was clearly differentiated from another primary biliary tract tumour. No patient had concomitant cirrhosis of the liver, but five had previous cholecystectomies.
The anatomic origin of cancer could be clearly distinguished in only 16 of the 27 cases (Table 2). Microscopic diagnosis was established in 18, of which 1 7 were reviewed by a second pathologist. In cases where it was not possible to make a histological confirmation, the diagnosis was based on a combination of radiological and intraoperative observations.
The types of treatment given and their outcomes are listed in Table 3. There was no significant difference in survival between patients who were treated by Stent or surgery alone. Of the 15 surgical procedures, two patients with attempted resection were lost to follow-up one month post surgery. The remaining operative procedures consisted of the Longmire operation (10 patients), left hepatic lobar resection (one patient), a Whipple's operation (one patient) and multiple bypass procedure (one patient). Of these 13 patients, three also received 4000 rads of cobalt therapy, and two had additional drainage procedures at a later date post-

DISCUSSION
There are three features of interest in this study. First, the two case reports highl ight possihle contrasts between younger and o lder patients wit h cholangiocarcinoma. Second, t he series ra ises discussion about possible underlying ill nesses wh ich may predispose to cholangioca rcinoma. Fina ll y, treatment and outcome in this series can be compared with the current experience in the literature.
In the present series, 7.4% of patients were younger than 30 years old, and the mean age was 6 5. l, comparable with that found in the li terat ure ( 1-6). A lthough there was more associated illness, the outcomes in the two young patients were not different from the group.  Previously associated conditions are listed in T..ible 4. The prevalence of 14.8% noted in the present series compares well with the 10% quoted in the literature for North America (7) . Although gallstones and other cancers were noted at 25.9% in the present series, these conditions ( with the exception of hepatolithiasis) are not thought to predispose to biliary cancer (26). In southeast Asia, liver flukes are also considered important (8)(9).
Association with ulcerative colitis is well established and estimated to be 0.4 to 1.6% (11,12). Recently, cholangiocarcinoma was also described in Crohn's disease ( 13,14 ). While sclerosing cholangitis is considered an antecedent, it is not a requirement (15). As well, the tumour has a variable time course with inflammatory bowel disease activity.
Salmonella carriers appear to have a higher risk for biliary cancer (16, l 7). However, the best documentation for progression to cholangiocarcinoma from the carrier state occurs in a single case report ( 18). Case l was likely a carrier, since both stool cultures and bile cultures were present with the same strain of salmonella in the absence of acute gastrointestinal symptoms. Furthermore, no other associated conditions were found. the authors are not aware of ascaris causing this neoplasm, and no eggs or worms were found at surgery.
Although choledochal cysts usually present in childhood (4,19), as in the single case, up to 20% may occur in adults (4,20). A triad of right upper quadrant mass, pain and intermittent jaundice occurs in 20% (21). Cholangiocarcinoma may occur in any portion of the dilated biliary tree and usually arises following incomplete surgical manipulation (4 ).
TREATMENT AND OUTCOME Prognosis is poor, and dependent on factors listed in Table 5 (1,7,10,22). Surgical management is dictated by site, with distal lesions being more amenable (23,24). In general, 15 to 61 % of tumours are resectable. While 100% of distal sites are amenable to surgery, only 33 and 10% of lesions, respectively, located in the middle or hilar biliary tree, are thus manageable (3,(22)(23)(24). More recently, an aggressive approach for hilar lesions, including anastomosis of the intrahepacic ducts with a defunctional enteric link, has had a marginal impact on survival (5,(25)(26)(27). In the current series, resection was attempted in only 48%, although two-thirds of the patients had surgery. The finding that the majority of tumours (56%) were in a hilar location contributed co the low rate of attempted resection.
Polypoid (28) and squamous cell cancers (29) both appear also to contribute to better survival than nodular, sclerosing or diffusely infiltrating types.
In the hope of avoiding high postoperative morbidity and mortality there is a search to better define resectabi Lity. While Comprodon (6) outlined an intraoperative approach prior to attempted resection, the increased use of nondirect visualization of the biliary tree recently prompted Lynn et al (30) to outline a radiological approach. In the latter study, proximal and mid duct tumours proved unresect- able. These results, however, need to be better refined in view of the 10 and 33% respective resectability rates reported by Alexander et al (3) for the same lesions. Funhermore, in cases where resection is not possible, either endoscopically or surgically placed scents appear to improve quality of life over more definitive surgically palliative operations (31,32).
Other modalities of therapy are not well established. Iridium or cobalt therapy can prolong median survival co 11 months (1). However, morbidity is substantial. Iwasaki (30) reported that intraoperative electron beam radiation resulted in a 17% two year survival versus 9% without such treatment (38).
Single agent therapy with mito• mycin C or 5-fluorouracil, or combina, tion with bis-chloronitrosourea, adriamycin and ftorafur showed a 30% response rate and a median prolongation of survival by 9.5 months (l). Jn another small study, external radiation was combined with adriamycin, 5fluorouracil and 131 I labelled anttcarcinocmbryonic antigen. However, only 7.4% complete and 25.9% partial remissions were achieved (34 ). No unified consensus of opinion exists on the use of such therapy at this time.

CONCLUSION
In summary, cholangiocarcinoma remains a poorly treatable neoplasm. The present survey found 14.8% of patients to have associated predisposing disease, and another 25.9% gallstones or other cancers occurring synchronously or rnetachronously. In this series, two patients were younger than 30 years old. Both had associated conditions and their courses were not dif-ferent from the rest. In the survey, 48% of patients were resected, and there is a possibility that pcrioperative radiotherapy may be useful. The literature review also suggests that at this time surgical resection of well defined lesions offers the best chance for prolonged survival. The role of adjuvanr therapy, although hopeful, is not settled.