found in the pancreatic juice of patients with chronic pancreatitis. This may relate to K-ras mutations in areas of duct hyperplasia [41]. Over a 2-year follow-up a minority develop pancreatic carcinoma [40]. Pathology Histologically, the tumour is an adenocarcinoma, whether arising from pancreatic duct, acinus or bile duct. The ampullary tumours have a papillary arrangement and are often of low-grade malignancy; fibrosis is prominent. They tend to be polypoid and soft, whereas the acinar tumours are infiltrative, large and firm. Obstruction of common bile duct This results from direct invasion causing a scirrhous reaction, from annular stenosis, and from tumour tissue filling the lumen. The duct may also be compressed by the tumour mass. The bile ducts dilate and the gallbladder enlarges. An ascending cholangitis in the obstructed duct is rare. The liver shows the changes of cholestasis. Pancreatic changes The main pancreatic duct may be obstructed as it enters the ampulla. The ducts and acini distal to the obstruction dilate and later rupture, causing focal areas of pancreati- tis and fat necrosis. Later all the acinar tissue is replaced by fibrous tissue. Occasionally, particularly in the acinar type, fat necrosis and suppuration may occur in and around the pancreas. Diabetes mellitus or impaired glucose tolerance is found in 60–80% of patients. Apart from destruction of insulin-producing cells by the tumour, this may be due to production of islet amyloid polypeptide (IAPP) by islet cells adjacent to the tumour [36]. Spread of the tumour Direct extension in the wall of the bile duct and infiltra- tion through the head of the pancreas is common with the acinar although not with the ampullary type. The second part of the duodenum may be invaded, with ulceration of the mucosa and secondary haemorrhage. The splenic and portal veins may be invaded and may thrombose with resultant splenomegaly. Involvement of regional nodes is found in approxi- mately a third of operated cases. Perineural lymphatic spread is common. Blood-borne metastases, with secon- daries in liver and lungs, follow invasion of the splenic or portal veins. There may also be peritoneal and omental metastases. Clinical features Both sexes are affected, but males more frequently than females in a ratio of 2:1. The sufferer is usually between 50 and 69 years old. The clinical picture is a composite one of cholestasis with pancreatic insufficiency, and the general and local effects of a malignant tumour (fig. 36.1). Jaundice is of gradual onset, progressively deepening, but ampullary neoplasms can cause mild and intermit- tent jaundice. Itching is a common but not invariable feature, and when present comes after jaundice. Cholan- gitis is unusual. Cancer of the head of the pancreas is not always pain- less. Pain may be experienced in the back, the epigas- trium and right upper quadrant, usually as a continuous distress worse at night and sometimes ameliorated by crouching. It may be aggravated by eating. Weakness and weight loss are progressive and have usually continued for at least 3 months before jaundice develops. Although frank steatorrhoea is rare, the patient often complains of a change in bowel habit, usually diarrhoea. Vomiting and intestinal obstruction follows invasion of the second part of the duodenum in 15–20% of patients. Ulceration of the duodenum can erode a vessel with haematemesis or, more commonly, occult bleeding. Difficulty in making a diagnosis may make the patient depressed. It then becomes easy to believe mistakenly, that the patient is psychoneurotic. Examination. The patient is jaundiced and shows evi- dence of recent weight loss. Theoretically, the gallblad- der should be enlarged and palpable (Courvoisier’s law). In practice, the gallbladder is only felt in about half the patients, although at subsequent laparotomy a dilated gallbladder is found in three-quarters. The liver is enlarged with a sharp, smooth, firm edge. The pancreatic tumour is usually impalpable. The spleen is palpable if involvement of the splenic vein has caused thrombosis. Peritoneal invasion is fol- lowed by ascites. Lymphatic metastases are more usual with cancer of the body rather than head of the pancreas [51]. Occa- sionally, however, axillary, cervical and inguinal glands may be enlarged and Virchow’s gland in the left supra- clavicular fossa may be palpable. Sometimes, widespread venous thromboses simulate thrombophlebitis migrans. Investigations Glycosuria occurs in 60–80% and with it there is an impaired oral glucose tolerance test. Blood biochemistry. The serum alkaline phosphatase level is raised. The serum amylase and lipase concentra- 640 Chapter 36 tions are sometimes persistently elevated in carcinoma of the ampullary region. Hypoproteinaemia with, later, peripheral oedema may be found. There is no reliable serum tumour marker with suffi- cient specificity or sensitivity. Using a cut-off of 70U/ml (almost twice the upper limit of normal), CA 19-9 has the greatest sensitivity (around 70%) and specificity (90%) of current markers for carcinoma of the pancreas [14]. However its sensitivity in the detection of early tumour is lower [22]. It can be elevated in benign biliary obstruction. Haematology. Anaemia is mild or absent. The leucocyte count may be normal or raised with a relative increase in neutrophils. The erythrocyte sedimentation rate is usually raised. Differential diagnosis The diagnosis must be considered in any patient over 40 years with progressive or even intermittent cholesta- sis. The suspicion is strengthened by persistent or unexplained abdominal pain, weakness and weight loss, diarrhoea, glycosuria, positive faecal occult blood, hepatomegaly, a palpable spleen or thrombophlebitis migrans. Radiology Most scanning techniques can detect pancreatic masses with high accuracy in specialist units. There are data supporting transabdominal ultrasound, spiral (helical) CT, dual-phase (arterial and venous) spiral CT, MRI, endoscopic ultrasound and PET scanning. The most effective initial technique is helical, dual-phase CT (see fig. 32.5) which has an accuracy of over 90% for tumours greater than 1.5cm and 70% for smaller tumours [24]. This technique is widely available with expertise in interpretation [19]. MRI with angiography (gadolinium enhancement) and endoscopic ultrasound have a similar accuracy in some centres [2, 4, 16], but these techniques and expertise are not as widely available as spiral CT. Scanning may also show dilatation of bile ducts and pancreatic duct, hepatic metastases and local spread of the primary lesion. Percutaneous ultrasound or CT-guided fine-needle aspiration of the pancreatic mass is safe and has a sensi- tivity of over 90% in some units. There is a small risk of seeding of tumour cells along the needle track. ERCP can usually demonstrate the pancreatic and bile ducts, allow biopsy of any ampullary lesion (fig. 36.2), and provide bile or pancreatic juice or brushings from the stricture for cytological examination (fig. 36.3). The appearance of the bile duct and/or pancreatic duct stric- ture (double duct sign) gives a good indication of the underlying malignant cause of the stricture (see fig. 32.12a) but occasionally appearances are deceptive [31] and tissue diagnosis should be sought. Biliary brush cytology has a sensitivity of around 60% for pancreatic carcinoma [23, 46]. Unusual tumours such as lymphoma need to be identified since they may respond to specific therapy. In the patient with vomiting, barium meal and/or endoscopy will show the extent of duodenal invasion and obstruction. Tumour staging This gives an indication of whether the tumour is resectable or not. Clinical evidence, chest X ray, ultra- sound or CT will show obvious metastatic disease. Dual or triple-phase spiral CT is highly accurate in predicting irresectability (approximately 90%) [24] but Diseases of the Ampulla of Vater and Pancreas 641 Fig. 36.2. Abnormal ampulla at ERCP. Note irregular surface with nodularity. Biopsy showed adenocarcinoma. Fig. 36.3. Brush cytology taken from a low common bile duct stricture. There is a sheet of benign biliary epithelial cells and above this a small group of large polymorphic cells characteristic of adenocarcinoma. is less accurate in predicting resectability. Features suggesting irresectability are local extension of tumour, encasement of extra-pancreatic arteries or veins, inva- sion of adjacent organs and lymph node metastases (more than an isolated solitary node). Most irresectable lesions (70%) have three or four of these features — the minority having only one or two. Spiral CT may also show hepatic metastases but the detection rate is higher when combined with arterioportography. Endoscopic ultrasound has a similar accuracy as dual phase helical CT in assessing irresectability, but expertise is not as widely available [24]. Experience with MRI is growing but it remains second choice to helical dual-phase CT. For vascular involvement these techniques can give the same information as digital subtraction angiography (DSA) which is now used only when the data from scan- ning is inconclusive or conflicting. Laparoscopy is valuable to show and biopsy minute hepatic metastases and peritoneal and omental seedings. Negative results from laparoscopy, CT and angiography correspond to a 78% resectability rate [51]. Prognosis The prognosis of pancreatic carcinoma is grave. After biliary bypass surgery the mean survival is about 6 months. The acinar type carries a worse prognosis than the ductal type because regional lymph glands are involved earlier. Only the minority of tumours, between 5 and 20%, are resectable. Resection has had an operative mortality of approxi- mately 15–20%, but recent reports have shown this to fall to 5% and less in specialist centres with a few expert surgeons performing more operations [14]. A recent report from a superspecialist unit of zero mortality after 145 consecutive pancreatico-duodenal resections is exceptional [10]. Coincident with reduced operative mortality has been a rise in reported 5-year survival to around 20%. This may reflect earlier detection of disease through the newer scanning techniques, or selection of patients with less extensive spread of disease. Disease recurrence, however, remains a problem [14]. Total pancreatectomy does not lead to longer survival than the less extensive Whipple’s procedure and produces exocrine insuffi- ciency and brittle diabetes. The overall outlook for carcinoma of the pancreas however, is grim with only 23 of 912 patients with carci- noma of the pancreas in one series surviving 3 years and only two of these being considered cures [11]. Prognosis for carcinoma of the ampulla is better. 85% or more of patients survive 5 years after resection if the tumour has not spread beyond the margins of the sphincter of Oddi. With more extensive tumour the 5-year survival falls to 11–35% [15, 52]. Treatment Resection A decision to attempt resection depends on the clinical state of the patient and the staging of the tumour derived from radiological imaging. Difficulties in removal arise because of the inaccessibility of the pancreas on the pos- terior wall of the abdomen in the vicinity of vital struc- tures. The resectability rate is therefore low. The classical procedure is pancreatico-duodenectomy (Whipple’s operation) which is performed in one stage with removal of related regional lymph nodes, the entire duodenum and the distal third of the stomach. This operation was modified in 1978 [49] to preserve antral and pyloric function (pylorus-preserving pancreatico- duodenectomy). This reduces post-gastrectomy symp- toms and marginal ulceration, and improves nutrition. Survival is the same as those having the classical proce- dure. The continuity of the biliary passages is restored by anastomosis of the common bile duct with the jejunum. Pancreatico-jejunostomy drains the duct of the remain- ing pancreas. The continuity of the intestinal tract is restored by duodeno-jejunostomy. Frozen section examination of the resection margins is mandatory. Prognostic factors are tumour size, resection margin and lymph node status [14]. The best indicator is lymph node histology. If negative at resection, 5-year survival is 40–50%, compared with 8% in those with nodes positive for metastasis [9]. Prognosis is also related to whether or not there is histological evidence of vascular invasion (median survival 11 vs. 39 months). Carcinoma of the ampulla is also treated by pancre- atico-duodenectomy. Local resection (ampullectomy) is an alternative in selected patients with premalignant or malignant ampullary lesions [5]. Endoscopic photody- namic therapy has produced remission or reduced tumour bulk in a series of patients with ampullary carci- noma unsuitable for surgery [1]. This technique uses endoscopic delivery of red light (630nm) to tumour sen- sitized with haematoporphyrin given intravenously. Palliative procedures The choice lies between surgical bypass and endoscopic or percutaneous trans-hepatic insertion of an endopros- thesis (stent). Palliative surgical biliary bypass is an option in irre- sectable patients with a predicted longer survival. For the jaundiced patient with vomiting due to duodenal 642 Chapter 36 obstruction, choledocho-jejunostomy with gastroen- terostomy is necessary. Gastric outlet and duodenal stenosis can be treated by endoscopically or radiologi- cally placed expandable mesh metal stents [33, 43] although experience with this technique is limited. For the patient with bile duct obstruction alone, some argue for prophylactic gastric bypass surgery at the time of biliary bypass but most would make this decision at the time of operation, according to the size of the tumour. Endoscopic stent insertion (fig. 36.4) is successful in up to 95% of patients (60% after the first session) and has a lower 30-day mortality than surgical bypass [42]. When the endoscopic approach fails, the percutaneous, or com- bined percutaneous/endoscopic approach can be used (Chapter 32). Percutaneous stent insertion (see fig. 32.21) has a similar mortality, early morbidity and mean survival time (19 vs. 15 weeks) to palliative surgery partly due to the com- plications of the trans-hepatic approach (haemorrhage, bile leakage) [7]. Endoscopic stent insertion has a lower complication rate and mortality than the percutaneous route [44]. Within 3 months of insertion 20–30% of plastic stents need to be replaced because of obstruction by biliary sludge. Metal mesh expandable stents can be inserted endoscopically or percutaneously (see fig. 32.17). They remain patent significantly longer than plastic stents (mean 273 vs. 126 days) [12]. However, because of their cost, they are best restricted to those patients with irre- sectable peri-ampullary carcinoma who at the time of first stent exchange because of blockage are judged likely to have slower progression and a longer survival [35]. This may be predicted to some extent by tumour size and weight loss [39]. If plastic stents are used, elective exchange of the stent every 3 months gives patients a longer complication-free interval than those having stent exchange only once blockage occurs [38]. The choice between surgical and non-surgical relief of biliary obstruction depends upon the expertise available and the clinical status of the patient. The non-surgical insertion of a stent is particularly applicable to older, poor-risk patients especially when a large, clearly inoperable pancreatic mass has been imaged or where there is extensive metastatic disease. For the younger patient with irresectable disease, surgi- cal bypass should still be considered if longer than average survival is expected. With all the approaches now available, no patient with carcinoma of the pancreas should die jaundiced or with intolerable itching. Chemotherapy: radiotherapy Pre-operative adjuvant chemotherapy and radiotherapy have produced disappointing results. Selected patients may benefit from adjuvant combined radiotherapy and chemotherapy after radical resection [20]. For patients with irresectable tumour many chemotherapeutic regimes have been studied in randomized trials [14]. 5- fluorouracil (5-FU) has been used widely. Recent data suggest that treatment with gemcitabine may have some benefit on survival and the alleviation of disease-related symptoms [8]. Ideally all patients should participate in comparative studies. Otherwise gemcitabine may be considered for patients with advanced pancreatic car- cinoma with or without metastases, who are still self- caring [14, 32]. For localized disease, radiotherapy and concomitant 5-FU is an alternative [14]. In patients who are no longer self-caring, management should focus on palliative measures rather than aggressive chemoradia- tion or chemotherapy. For patients with pain, coeliac plexus block may be Diseases of the Ampulla of Vater and Pancreas 643 Fig. 36.4. Polyethylene 10 French endoprosthesis inserted across low common bile duct stricture by the endoscopic route. Note good flow of contrast into duodenum and decompressed biliary system. more effective than oral or parenteral analgesia. Benefit is more immediate [37]. However, although coeliac plexus block either done percutaneously under X-ray screening or at operation can reduce pain for a few months, pain may return in over half of patients [27]. Benign villous adenoma of the ampulla of Vater This leads to biliary colic and obstructive jaundice. The ampullary tumour is seen and biopsied at ERCP. Dysplasia may be present on biopsy. Carcinoembry- onic antigen (CEA) and CA19-9 are found on immuno- histochemistry [53]. These lesions should be regarded as potentially premalignant. Local resection or pancreatico- duodenectomy is indicated [5]. In patients unfit for surgery, stenting is palliative. Endoscopic ablation may be successful using laser, monopolar or bipolar coagula- tion, or photodynamic therapy [1, 34]. Cystic tumours of the pancreas [18] These may be benign or malignant and include cystic adenocarcinoma, cystic adenoma (serous and mucinous) and papillary cystic tumours. They may be misdiag- nosed as pseudocysts. 40% of patients are asymptomatic. Work-up is by CT, endoscopic ultrasound, angiography and ERCP. Cyst fluid analysis (cytology, tumour markers) may be valuable in differentiating the type of tumour [26]. Around 40% of lesions are malignant. In general, resection should be attempted. Frozen and even routine histology may be misleading. Mucinous cystic neoplasm should be considered potentially malignant. Endocrine tumours of the pancreas [3, 47] These include insulinoma (70%), gastrinoma (20%), vaso-active intestinal polypeptide-secreting tumour (VIPoma), glucagonoma, polypeptide-secreting tumour (PPoma) and somatostatinoma. Some may be non-func- tioning [6]. They present with either the systemic effects of the hormone released or a mass effect with pain or jaundice as with pancreatic carcinoma. A variable pro- portion are malignant, depending on the endocrine type. Treatment is by surgical resection or debulking, and medical measures to counter the effect of any hormone released. Survival depends on the tumour type and stage. Chronic pancreatitis Pancreatitis, usually of alcoholic aetiology, can cause narrowing of the intra-pancreatic portion of the common bile duct. The resultant cholestasis may be transient during exacerbations of acute pancreatitis. It is presum- ably related to oedema and swelling of the pancreas. More persistent cholestasis follows encasement of the intra- and peri-pancreatic bile duct in a progressively fibrotic pancreatitis. Pseudocysts of the head of the pan- creas and abscesses can also cause biliary obstruction and persistent cholestasis. Bile duct stenosis affects about 8% of patients with chronic alcoholic pancreatitis and this figure would be higher if more cholangiograms were done. It should be suspected if the serum alkaline phosphatase is more than twice elevated for longer than 1 month. ERCP shows a smooth narrowing of the lower end of the common bile duct, sometimes adopting a ‘rat tail’ configuration (fig. 36.5). The main pancreatic duct may be tortuous, irregu- lar and dilated. Pancreatic calcification may be present. Liver biopsy shows portal fibrosis, features of biliary obstruction, and sometimes biliary cirrhosis. Features of alcoholic liver disease are unusual. Hepatic fibrosis regresses after biliary decompression [21]. Splenic vein thrombosis is a complication of chronic pancreatitis. Management Early diagnosis of a biliary stricture due to pancreatitis is essential as biliary cirrhosis and acute cholangitis can develop in the absence of clinical jaundice. If alcohol is responsible for the pancreatitis the patient must abstain completely. The place of surgery is controversial. Clinical, labora- tory and imaging data do not necessarily distinguish 644 Chapter 36 Fig. 36.5. ERCP in a patient with alcoholic chronic pancreatitis. Note the ‘rat tail’ narrowing of the distal common bile duct (arrow). those patients with significant bile duct obstruction from those with alcoholic liver disease or normal liver histol- ogy [25]. Liver biopsy is valuable in deciding whether surgical decompression of the bile duct is necessary. Plastic and metal mesh stents successfully relieve bile duct obstruction due to chronic pancreatitis [13], but longer-term data are needed to judge whether this is an appropriate method of treatment. Acute cholangitis, biliary cirrhosis and protracted jaundice are strong indi- cations for surgery [45]. Choledocho-enterostomy is the usual procedure. Obstruction of the common bile duct by enlarged lymph glands This is rare. The enlarged glands are nearly always metastatic, frequently from a primary in the alimentary tract, lung or breast, or from a hepato-cellular carcinoma. Malignant glands in the porta hepatis are associated with deep jaundice, the main bile ducts usually being invaded rather than compressed. Secondary deposits in the hepatic parenchyma may also invade the bile ducts, causing segmental obstruction. Glands along the common duct may be enlarged in non-malignant conditions, but the bile duct usually escapes compression. Jaundice in infections such as tuberculosis, sarcoidosis or infectious mononucleosis is not obstructive but due to direct hepatic involvement or haemolysis. Glandular enlargement in the reticuloses does, very rarely, cause obstruction to the common bile duct, but jaundice complicating these diseases is more often due to hepatic parenchymal involvement, to increased haemolysis or loss of intra-hepatic bile ducts (Chapter 13). Other causes of extrinsic pressure on the common bile duct Duodenal ulceration This is an extremely rare cause of obstructive jaundice. Perforation, so that the ulcer impinges against the bile duct or causes adhesive peritonitis, may rarely result in biliary obstruction. This can also follow scarring as the ulcer heals or endoscopic sclerosis for bleeding. Duodenal diverticulum Diverticula of the duodenum are often found near the ampulla of Vater, but rarely cause obstruction of the bile duct. They are associated with an increased rate of gall- bladder and common bile duct stones, and the recur- rence of duct stones [54]. References 1 Abulafi AM, Allardice JT, Williams NS et al. Photodynamic therapy for malignant tumours of the ampulla of Vater. Gut 1995; 36: 853. 2 Adamek HE, Albert J, Breer H et al. Pancreatic cancer detec- tion with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: a prospective controlled study. Lancet 2000: 356; 190. 3 Aldridge MC. Islet cell tumours: surgical treatment. Hosp. Med. 2000; 61: 830. 4 Arslan A, Buanes T, Geitung JT. Pancreatic carcinoma: MR, MR angiography and dynamic helical CT in the evaluation of vascular invasion. Eur. J. Radiol. 2001; 38: 151. 5 Asbun HJ, Rossi RL, Munson JL. Local resection for ampullary tumours: is there a place for it? Arch. Surg. 1993; 128: 515. 6 Bartsch DK, Schilling T, Ramaswamy A et al. Management of nonfunctioning islet cell carcinomas. World J. Surg. 2000; 24: 1418. 7 Bornman PC, Harries-Jones EP, Tobias R et al. Prospective controlled trial of transhepatic biliary endoprosthesis vs. bypass surgery for incurable carcinoma of head of pancreas. Lancet 1986; i: 61. 8 Burris III HA, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a ran- domised trial. J. Clin. Oncol. 1997: 15; 2403. 9 Cameron JL, Crist DW, Sitzman JV et al. 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Endosc. 2001; 54: 56. 646 Chapter 36 Benign lesions of the gallbladder At ultrasound, polypoid lesions of the gallbladder are occasionally seen and there is usually concern as to their nature and how to manage them. The vast majority are benign. They may be true tumours or pseudo-tumours. True tumours comprise adenoma, lipoma and leiomy- oma. Pseudo-tumours include cholesterol polyps, inflammatory polyps and adenomyomatosis. These lesions are seen most often as an echogeneic focus that projects into the gallbladder lumen, does not cast an acoustic shadow, and does not move when the patient is moved (unlike a stone). The diagnostic accu- racy of ultrasound for the commonest lesions is 50–90% depending on the pathology [34]. Cholesterol polyps are usually multiple, with a higher echogenicity than liver, a pedicle and a mulberry-like surface [34]. They may contain a hyperechoic spot. Pathologically they consist of hypertrophied villi laden with cholesterol. Adenoma is seen as a polypoid lesion which on ultra- sound has an echogenicity similar to the liver, a smooth surface and usually no pedicle [34]. 80%–90% of gallbladder polypoid lesions do not change in size on follow-up scans [41, 57]. However, they cause concern because of the low chance of malignancy in adenomas. Cholecystectomy will be done for the symptomatic patient. This is also appropriate for the lesion greater than 10mm in diameter, where the risk of malignancy is greater [34]. Other features of malignant tumour are a sessile lesion, isoechoic with the liver, growing rapidly on serial ultrasounds. Patients with a smaller lesion without these features should undergo a second scan. Some lesions disappear but the majority remain, and these patients may be offered a cholecystectomy for peace of mind. Alterna- tively, a repeat scan is done at 6-monthly intervals to detect any change in size [39]. In practice ultrasound lesions less than 10mm in diameter with benign appear- ances in an asymptomatic patient tend to be treated con- servatively but follow-up scanning is important. If the result of trans-abdominal ultrasound is inconclusive, endoscopic ultrasound if available is useful with a diag- nostic accuracy for neoplastic lesions of 80% [10]. Carcinoma of the gallbladder [1] This is an uncommon neoplasm. Gallstones coexist in about 75% of cases and chronic cholecystitis is a frequent association. There is a clear association with large, multi- ple gallbladder stones [62], but a causal relationship is unproven. The calcified (porcelain) gallbladder is particularly likely to become cancerous [51]. An anomalous pancre- atico-biliary ductal union, greater than 15mm from the papilla of Vater, is associated with congenital cystic dilatation of the common bile duct and with gallbladder carcinoma [40]. Regurgitation of pancreatic juice may be tumorigenic. The common gallbladder cholesterol polyps are not precancerous. Chronic typhoid infection of the gallbladder increases the risk of gallbladder carcinoma by 167-fold [6], empha- sizing the need for antibiotic treatment to eradicate the chronic typhoid and paratyphoid carrier state, or for elective cholecystectomy. Papillary adenocarcinoma starts as a wart-like excres- cence. It grows slowly into, rather than through, the wall until a fungating mass fills the gallbladder. Mucoid change is associated with more rapid growth, early metastasis and gelatinous peritoneal carcinomatosis. Squamous cell carcinoma and scirrhous forms are recog- nized. The anaplastic type is particularly malignant. The most common tumour is a differentiated adenocarci- noma [1, 16] which may be papillary. The tumour usually arises in the fundus or neck, but rapid spread may make the original site difficult to locate. The rich lymphatic and venous drainage of the gallbladder leads to early spread to related lymph nodes, causing cholestatic jaundice and widespread dissemina- tion. The liver bed is invaded and there may also be local spread to the duodenum, stomach and colon resulting in fistulae or external compression. Clinical. The patient is usually an elderly, white female, complaining of pain in the right upper quadrant, nausea, vomiting, weight loss and jaundice. Sometimes an unsuspected carcinoma is found in a cholecystectomy specimen at histology. These small lesions may not even be recognized at the time of operation [13]. 647 Chapter 37 Tumours of the Gallbladder and Bile Ducts Examination may reveal a hard and sometimes tender mass in the gallbladder area. Serum, urine and faeces show the changes of cholestatic jaundice if the bile duct is compressed. Ultrasound scanning shows a mass in the gallbladder lumen or totally replacing the gallbladder. With early lesions the differentiation between gallbladder carci- noma and a thickened wall due to acute or chronic chole- cystitis is difficult. CT may also show a mass in the area of the gallblad- der. Ultrasound and CT detect carcinoma of the gallblad- der in 60–70% of cases [45]. By the time an abnormality is shown by ultrasound or CT, extension is likely and the chance of total removal low. Endoscopic ultrasound images correlate with histo- logical depth of invasion and are useful in staging [23]. ERCP shows external compression of the bile duct in the jaundiced patient. Angiography shows displacement of hepatic and portal blood vessels by the mass. In only 50% of patients is a correct pre-operative diag- nosis made [12]. Prognosis This is generally hopeless because the majority are inop- erable at the time of diagnosis. Distant metastases are already present in 50% of cases [16]. The only long-term survivors are those in whom the tumour was found inci- dentally at the time of cholecystectomy for gallstones (carcinoma in situ). Median survival from diagnosis is 3 months, with only 14% alive at 1 year [12]. Patients with papillary and well- differentiated adenocarcinomas have longer survival than those with tubular and undifferentiated types [28]. The results of radical resection including partial hepa- tectomy and radical lymphadenectomy are conflicting [9, 16] with some series showing no survival benefit and others claiming increased survival. Treatment Cholecystectomy has been recommended for all patients with gallstones in an effort to prevent the development of carcinoma in the gallbladder. This seems drastic for a common condition, and would lead to a large number of unnecessary cholecystectomies. The pre-operative diagnosis of carcinoma of the gall- bladder should not preclude laparotomy although the results of surgical treatment are disappointing. Radical resection including partial hepatectomy has been attempted but with unsatisfactory results and no con- vincing evidence of improved survival [16]. The same applies to radiotherapy and chemotherapy [1]. Endoscopically or percutaneously placed biliary pros- theses relieve bile duct obstruction. Other tumours Rarely other tumours develop in the gallbladder including leiomyosarcoma, rhabdomyosarcoma, oat cell carcinoma and carcinoid tumours. Benign tumours of the extra-hepatic bile duct These extremely rare tumours usually remain unde- tected until there is evidence of biliary obstruction and cholangitis. They are rarely diagnosed pre-operatively. Recognition is important as resection is curative. Papilloma is a polypoid tumour which projects into the lumen of the common bile duct. It is a small, soft, vascu- lar tumour, which may be sessile or pedunculated. These tumours may be single or multiple; they may be cystic. Occasionally they undergo malignant change. Cholan- giography may show a smooth mass projecting into the bile duct. Mucus secretion from the tumour can cause obstructive cholangitis. Adenomyoma can be found anywhere in the biliary tract. It is firm and well circumscribed and varies in size up to 15cm in diameter. It is cured by resection [11]. Fibroma is small and firm and causes early bile duct obstruction. Granular cell tumour is of mesenchymal origin. It affects young women, usually black, causing cholestasis [5]. It must be distinguished from cholangiocarcinoma or localized sclerosing cholangitis. Tumours are uniformly resectable and curable. Carcinoma of the bile duct (cholangiocarcinoma) Carcinoma may arise at any point in the biliary tree from the small intra-hepatic bile ducts to the common bile duct (fig. 37.1). The incidence of intra-hepatic cholangiocarcinoma is increasing. Studies from England and Wales [59] and the USA[48] show a 10-fold increase between the early 1970s and the mid-1990s. The explanation is unclear. Although improved diagnostic techniques for cholangiocarcinoma and primary sclerosing cholangitis may have played a part, they do not alone explain the marked increase in incidence and mortality. Mortality from extra-hepatic cholangiocarcinoma fell over the same period. The treatment depends on the site. Resection is the rule for extra-hepatic tumours. For hilar cholangiocarci- noma surgical resection should always be considered but requires particular expertise because of the inaccessi- bility of hilar tumours, the proximity of the hepatic artery and portal vein and the need for hepatic resection in some patients. Even if not curative, surgical treatment may prolong survival with a good quality of life. 648 Chapter 37 Suspicion of cholangiocarcinoma, for example after ultrasound scan, should lead to referral to a specialist unit. This is to co-ordinate the work-up to evaluate resectability of the tumour. Modern CT techniques and MRI with MR cholangiography allow a high degree of non-invasive evaluation. The necessity and timing of invasive investigations depends on clinical circum- stances. ERCP and non-operative drainage of bile per- cutaneously or after ERCP frequently introduce sepsis which may compromise later treatment [29, 42]. These aspects emphasize the importance of a multidisciplinary approach. In those who are inoperable, biliary drainage by inter- ventional radiologist or endoscopist relieves pruritus and usually jaundice to allow satisfactory palliation. Associations Bile duct cancer is associated with ulcerative colitis with or without sclerosing cholangitis (Chapter 15). The majority of patients with primary sclerosing cholangitis who develop cholangiocarcinoma have ulcerative colitis. Patients with primary sclerosing cholangitis and ulcerative colitis who also have colorectal neoplasia (dysplasia/carcinoma) are at greater risk of cholangio- carcinoma than those without colonic neoplasia [4]. In a group of 70 patients with primary sclerosing cholangitis followed prospectively for a mean of 30 months, 15 patients died of liver failure. Five of 12 patients (40%) having an autopsy had cholangiocarci- noma — 7% of the total group [54]. Biliary malignancy is not necessarily a late complica- tion of primary sclerosing cholangitis. 30% of patients in one series had a diagnosis of cholangiocarcinoma made within 1 year of the first evidence of underlying liver disease based on abnormal liver function tests [37]. Clinical features associated with malignancy were epigastric pain, weight loss and raised CA 19-9 and carcinoembryonic antigen (CEA) [37]. All members of the congenital fibropolycystic family may be complicated by adenocarcinoma (Chapter 33). These include congenital hepatic fibrosis, cystic dilata- tion (Caroli’s syndrome), choledochal cyst, polycystic liver and von Meyenburg complexes. Cholangiocarci- noma may be associated with biliary cirrhosis due to biliary atresia. The liver fluke infestations of the Orient may be com- plicated by intra-hepatic (cholangiocellular) cholangio- carcinoma. In the Far East (China, Hong Kong, Korea, Japan), where Clonorchis sinensis is prevalent, cholangio- carcinoma accounts for 20% of primary liver tumours. These arise in the heavily parasitized bile ducts near the hilum. Opisthorchis viverrini infestation is important in Thai- land, Laos and western Malaysia [35]. These parasites induce DNA changes and mutations through the pro- duction of carcinogens and free radicals, and the stimu- lation of cellular proliferation of intra-hepatic bile duct epithelium [46]. The risk of extra-hepatic bile duct carcinoma is signifi- cantly lower 10 years or more after cholecystectomy, sug- gesting a link with gallstones [17]. Pathology The confluence of the cystic duct with the main hepatic duct or the right and left main hepatic ducts at the porta hepatis are common sites of origin (fig. 37.1). Tumours of the hepatic ducts extend into the liver. They cause com- plete obstruction of the extra-hepatic bile ducts with intra-hepatic biliary dilatation and enlargement of the liver. The gallbladder is collapsed and flaccid. If the tumour is restricted to one hepatic duct, biliary obstruc- tion is incomplete and jaundice absent. The lobe of the liver drained by this duct atrophies and the other hypertrophies. In the common bile duct the tumour presents as a firm nodule or plaque which causes an annular stricture which may ulcerate. It spreads along the bile duct and through its wall. Local and distant metastases, even at autopsy, are found in only about half of the patients. They involve peritoneum, abdominal lymph nodes, diaphragm, liver Tumours of the Gallbladder and Bile Ducts 649 U pp er third 58 % Middle third 17 % Lower third 18 % Diffuse 7 % Fig. 37.1. Site of cholangiocarcinoma. The majority occur in the upper third of the bile duct [60]. [...]... loss The blood is aspirated from the abdominal cavity, washed repeatedly, re-suspended and infused The hilar structures and vena cava above and below the liver are dissected The various vessels are crossclamped and divided to allow removal of the liver During the implantation of the new liver, it is neces- sary to occlude the splanchnic and vena caval circulations During this anhepatic phase, veno-venous... cava and aorta of the recipient The donor liver hypertrophies and the recipient’s own liver atrophies Complications, particularly portal vein thrombosis and primary graft non-function, are increased Auxiliary liver transplantation offers the possibility of a life-time free of immunosuppressive therapy This is discontinued when the host liver has recovered In time the auxiliary is likely to atrophy and. .. pooling in the lower part of the body and splanchnic congestion The cannulae are placed in the inferior vena cava (via the femoral vein) and the portal vein, and run to the subclavian vein The veno-venous bypass allows greater haemodynamic stability during the anhepatic phase of the operation Once all vascular anastomoses are completed, the preservation fluid is flushed out of the graft before opening the blood... procedures, the size of the donor liver should be matched to that of the recipient This is based on a body weight within 10 kg of the recipient Occasionally a small-sized liver is transplanted into a larger patient The donor liver increases in size at the rate of about 70 ml/day until it achieves the volume expected for the recipient’s size, age and sex [113] The recipient operation (fig 38.4) The average... ducts with at least three segments obstructed in the right lobe and the left hepatic system obstructed at the hilum If non-surgical drainage is to be done, these appearances favour drainage of the left- rather than the right-sided system (D, duodenum) (b) MRI scan shows a mass in the liver (arrow) above the hilum (c) Nonoperative drainage was chosen since the patient was considered inoperable ERCP shows... Non-alcoholic fatty liver disease (NAFLD) Fibro-lamellar carcinoma The tumour is localized to the liver and cirrhosis is absent This may be the best tumour candidate for transplantation The end-stage is macronodular fatty cirrhosis This is treated by transplantation, but 50% develop liver biopsy evidence of NAFLD post-transplant [79] Absolute and relative contraindications Epithelioid haemangio-endothelioma... the liver and intra-hepatic bile ducts This is of more value than the appearances of the extra-hepatic biliary tree below the stricture Angiography Digital subtraction angiography (DSA) shows the hepatic artery and portal vein and their intra-hepatic branches Its use depends upon the information derived from ultrasound, CT and MRI Diagnosis In the patient with deepening cholestatic jaundice the clinical... techniques and post-operative care, and to greater willingness to re-transplant after rejection Better immunosuppression has contributed Selection of patients The patient selected for transplant should suffer from irreversible, progressive disease for which there is no acceptable, alternative therapy The patient and the family must understand the magnitude of the undertaking and be prepared to face the difficult... antibodies and HIV testing should be done The donor operation is as follows The hepatic structures are dissected and the liver is pre-cooled through the portal vein with Ringer’s lactate and 100 0 ml of University of Wisconsin (UW) solution perfused through the aorta and portal vein A cannula in the distal inferior Hepatic Transplantation vena cava provides a vent for venous outflow After removal, the cold liver. .. mortality, but the worst long-term survival Carcinomatosis is the usual cause of death Tumour recurs in 60%, perhaps because of the immunosuppressants necessary to prevent rejection The peri-operative survival is 76%, but the 1-year survival only 50% and the 2-year survival 31% For all tumours transplanted, the overall actual 5-year survival is 20.4% Hepato-cellular carcinoma (Chapter 31) The tumour must . which there is no acceptable, alternative therapy. The patient and the family must understand the magnitude of the under- taking and be prepared to face the difficult early post- operative period and. on the clinical state of the patient and the staging of the tumour derived from radiological imaging. Difficulties in removal arise because of the inaccessibility of the pancreas on the pos- terior. incidence of intra-hepatic cholangiocarcinoma is increasing. Studies from England and Wales [59] and the USA[48] show a 1 0- fold increase between the early 1970s and the mid-1990s. The explanation