Tumors of the extrahepatic biliary radicals

TUMORS OF THE EXTRAHEPATIC 'BILIARY RADICALS WILLIAM P. LONGMIRErJR.

EDITORIAL COMMENT: The breadth of Doctor Longmire's literature review is reflected by citing Case IV in a publication by Doctor William Halsted of Baltimore in 1899,* wherein hepaticocholecystentostomy was suggested for bypass palliation. This is difficult to perform clinically; but an excellent result, credited initially to radiation therapy, occurred at M. D. Anderson Hospital where a spontaneous fistula from an accessory liver duct allowed bile to flow into the gallbladder and gave a patient with a hilar lesion relief from jaundice. Furthermore, in an experimental model at MDAH, three monkeys lived three years in good health after hepaticocholecystentostomy. At MDAH the procedure ofT-tube intubation has been plagued by cholangitis as· a complication. Of further note, of 22 patients with extrahepatic duct cancers, one was associated with ulcerative colitis. The reviewers laud Doctor William P. Longmire, Jr., for writing a precise and comprehensive treatise on the diagnosis and management of the complex extrahepatic bile duct tumors. ROBERT C. HICKEY, M.D.

"Halsted, William S.: Reference cited following text. 2

TABLE OF CONTENTS .

5

BENIGN TuMORS .

9

HISTORY.

.

.

Introduction Pathology . Clinical Presentation Diagnostic Procedures. Treatment. . . . . MALIGNANT EXTRAHEPATIC BILE DUCT TuMORS

Incidence

. . . . . .

9 9

10 10 11

12 12

Etiology. . . Pathology . . . . .

13 15 17

Clinical Course .'. . Special Diagnostic Tests Treatment

20 23 28

ANATOMICAL CONSIDERATIONS

42

SUMMARY.

3

TUMORS OF THE EXTRAHEPATIC 'BILIARY RADICALS WILLIAM P. LONGMIRErJR.

is Professor and former Chairman, Department of Surgery at the University of California School of Medicine, Los Angeles. Doctor Longmire received his M.D. degree from the Johns Hopkins Medical School in 1938. Prior to his current appointment, he served as Associate Professor of Surgery, the Johns Hopkins Medical School. Doctor Longmire has served as president of professional societies such as the American College of Surgeons and the American Surgical Association. His clinical and research interests have been in hepatobiliary surgery, gastric cancer and pancreatic disease.

IN PRESENTING 20 cases of primary carcinoma of the bile ducts seen at the Mayo Clinic from 1907 to 1921, Renshaw l stated, "Malignant conditions of the biliary ducts, being as a rule small, limited to the walls of the bile ducts and late to metastasize, should lend themselves readily to surgical treatment." In that statement lies the frustration so keenly experienced by every surgeon who has treated this disease, for the tumor certainly' would seem to have all of the characteristics that should make it amenable to surgical extirpation with excellent results. Early symptoms are produced as the bile duct is obstructed; the total tumor mass is usually quite small (not more than 2 - 3 cm in diameter, unless it is multicentric, which will be discussed), distant metastases are rare, and the tumor spreads primarily by direct extension. Yet cures following operation have been reported rarely, and those tumors that are cured are always located in the middle or lower third of the extrahepatic ductal system. Despite our inability to cure this disease, however, excellent palliation can be achieved, inasmuch as alleviation of the biliary obstruction alone-by anyone of a variety of procedures-provides almost completely pain-free symptomatic relief for a number of months. HISTORY

The first report of primary cancer of the common bile duct was made by Durand-Fardel2 in 1840. He described three cases of can5

eel' of the gallbladder, as well as one in which the tumor was localized at the common bile duct. In 1878, SchlippeP published an article in H andbuch der speziellen Pathologie und Therapie of von Ziemssen, reporting for the first time on cancer of the common hepatic duct. In it he recognized for the first time the predilection of cancer of the bile ducts for involvement of the proximal hepatic duct, a point that has been repeatedly confirmed and emphasized in countless cases published since that time. In 1889, Mussert compared the behavior of gallbladder cancer with the characteristics of 18 cases of primary cancer of the bile ducts that he collected from the literature. He made certain distinctions between the two diseases: (1) Carcinoma of the bile duct is less frequent than cancer of the gallbladder. (2) Unlike cancer of the gallbladder, it occurs equally in both sexes (most recent series report a 2: 3 female-to-male ratio). (3) The age of patients is about the same for both diseases. (4) Gallstones are rarer when the ducts are the seat of the disease. (5) The gallbladder is slightly enlarged and only by dilatation. (6) Metastasis is not common and not distant. (7) Adhesions, ulceration and perforation do not occur. (8) Jaundice is more common in bile duct than in gallbladder cases. (9) The sequelae of jaundice and accidental or intercurrent diseases are the cause of death. (10) A tumor (mass) is present in a smaller ratio of cases when the bile duct rather than gallbladder is the seat of disease; it is never as large as in cancer of the gallbladder. In Musser's collected series, the common duct was involved in 14 cases, with the growth situated at the duodenal orifice in 3 of these; the hepatic duct was involved in 4 (once with the cystic duct). Of 511 operations on the gallbladder· and bile ducts at the Mayo Clinic prior to March, 1903,6 were believed to have been performed for primary malignant neoplasms of the bile ducts. s One of the 7 cases Halsted presented in his discussion of surgery of the bile passages before the Surgical Section of the Suffolk District Medical Society in 18996 must surely have been a primary bile duct carcinoma, viz., case 4: "The entire common duct was impervious and reduced to a fibrous cord. The cystic duct, greatly narrowed, was probably impervious; the gallbladder and hepatic ducts were dilated." Such findings suggested to Halsted's facile mind a new operation - hepaticocholecystocholecystenterostomy: "It occurred to me that in case the gallbladder and hepatic ducts were both dilated, one might establish a fistulous communication between them, making an hepaticocholecystostomy and then immediately a cholecystenterostomy. However, when bile was at last reached, the patient was in such bad condi tion that the operation had to be terminated." In this same series of cases, Halsted also reported the successfullocal excision in 1898 of what he considered to be a carcinoma 6

of the papilla (case 2). Mayo5later described this case of Halsted's as the first successful excision of a carcinoma of the common bile duet. Mayo himself reported the local excision in 1901 of a similar "grayish white mass the size of the end phalanx of the forefinger strictly localized to the site of the papilla of the common duct" as the second successful removal of a common duct cancer. Both patients subsequently died of recurrent tumor, Halsted's in about 7 months and Mayo's in Ilf2 years. Both of these tumors would probably be classified today as carcinoma of the ampulla of Vater, rather than as carcinoma of the common bile duct. Stewart, Lieber and Morgan7 described 6 cases of carcinoma of the extrahepatic bile duets and were the first to present a comprehensive review of the clinical course and pathologic analysis of this disease. Of 309 cases reported at that time, they accepted 98 as having appropriate evidence to be so classified. An immediate postoperative mortality of 68% and an ultimate mortality of 98% of the 50 patients who underwent operations provide ample testimony to the dismal therapeutic outlook for this disease at that time. These cases are sufficiently rare that a preponderance of the meaningful information in this country has ~ppeared in series published by major surgical clinics, such as the reports from the Mayo Clinic ranging from Dr. W. J. Mayo's report in 1903 5 to the 63 cases of extrahepatic bile duet carcinoma described by Kuwayti and his associates in 1957.8 In 1949, Neibling, Dockerty and Waugh!) compared the frequency of carcinoma of the extrahepatic bile ducts with that of carcinoma of nearby structures, as dis-. cussed in the Mayo series. The extrahepatic bile duets wereaffeeted in 66 cases, the ampulla of Vater in 44 cases, the gallbladder in 107 cases and the pancreas in 521 cases. . Jaundice, pain and weight loss were the most frequently occurring symptoms; 26% of the tumors were located in the hepatic duets; 35% at the juncture of the common, cystic and hepatic duets; 32% in the common duet; and 3% in the cystic duct. No definite point of origin along the duct could be determined for 4% of the tumors, which were diffuse. All of the tumors were adenocarcinomas. In 90 cases, the grades for malignancy were evaluated as follows: grade 1, 18; grade 2, 41; grade 3, 23; grade 4, 8. From the material they studied, the authors concluded that the disease was rapidly fatal (mean survival after operation, 3 - 4 months) and that metastasis or extension occurred early in the disease. Even in a small group of cases evaluated before the development of jaundice, metastasis was present in 75%. Patients in this series lived longer if extirpation of the tumor was possible; however, this procedure could be successfully performed only in those rare situations in which extension of the tumor was absent. Sako and his colleagues lO reviewed 564 primary carcinomas of 7

the extrahepatic bile ducts reported in the world literature from 1935 through June, 1954, and added 6 cases of their own. Of the 570 tumors, 263 were located ator above the junction of the cystic and hepatic ducts. Histologically, the majority of the tumors were differentiated adenocarcinomas. The authors commented on the poor results of the various external drainages, shunts and anastomoses between the biliary tract and the gastrointestinal tract. The 172 patients treated surgically survived an average of 4.2 months. The difficulty of locating these tumors and correctly establishing the diagnosis at the time of operation, as well as the tendency to confuse them both grossly and microscopically with sclerosing cholangitis, was first emphasized by Altemeier and his colleagues II in 1957. They remarked that there was an unusual type of primary bile duct carcinoma arising in the major intrahepatic ducts at the hilus: "Its insidious nature, the ease with which it mimics other biliary tract disorders, and its relative inaccessibility to surgical approach are factors which have made diagnosis very difficult and frequently impossible until autopsy." They reported three cases of bile duct adenocarcinoma with surprisingly long survival times, repeated difficulties in establishing a correct diagnosis from biopsy specimens and clinical features that were suggestive of benign obliterative cholangitis rather than malignant disease. Ross, Braasch and Warren 12 reported in 1973 on 103 cases of carcinoma of the left and right hepatic ducts, the common hepatic duct and the common duct seen at the Lahey Clinic during a 15year period. They also emphasized the difficulty of establishing a correct histologic diagnosis at the time of an operation, inasmuch as these tumors frequently promote a marked fibroblastic reaction that mimics either biliary stricture otbenign sclerosing cholangitis both macroscopically and microscopically. Resection of the tumor, the only hope of cure, was possible in a mere 10% of patients; however, various decompressive procedures gave prolonged periods of palliation. Nine patients lived for 41f2 years or longer, and 2 of them lived for 9 years. Eight of the patients in their series also had ulcerative colitis, and 5 patients had previously undergone resection of a tumor elsewhere (3 for resection of colonic cancer, 1 for mixed tumor of the parotid, 1 for bronchial adenoma and 1 who developed a cystadenoma of the ovary 4 years after resection of the bile duct carcinoma). The anatomical relationships of the extrahepatic hilar structures were studied by Longmire and associates 13 in their report of 63 cases of carcinoma of the extrahepatic bile duets seen at the UCLA Hospital. The cases were divided for purposes of discussing treatment and prognosis into three general categories: (1) those located in the upper region, including the left and right hepatic 8

ducts, their confluence and the common hepatic duct; (2) those in the common duct from the region of the cystic duct down to the pancreas; and (3) those in the intrapancreatic portion of the common duct, not including tumors of the ampulla of Vater. Methods of resecting the hepatic inflow blood supply with the adjacent duct tumor, along with the distal hepatic parenchyma, were presented, and previous hepatic resections for bile duct carcinoma were reviewed. BENIGN TUMORS INTRODUCTION

Although this discussion is primarily concerned with the malignant lesions of the extrahepatic bile ducts, benign tumors, which are known to occur with considerable rarity, are included in the following section for completeness. In 1950, Chu H presented a case of fibroma of the extrahepatic biliary tract and reviewed the 26 case reports then available with adequate histologic confirmation to be considered true benign lesions of the extrahepatic ducts. Dowdy and associates l5 found 29 cases of benign lesions, excluding tumors of the ampulla of Vater, reported from 1950 to 1960. Hossack and Herron l6 discussed 1 such case and reviewed 19 additional cases reported between 1960 and 1970, bringing the total number of cases published up to that time to 76. PATHOLOGY

Eight different histologic types of tumors have been described: papilloma, (2) polyp, (3) adenoma, (4) fibroma, (5) adenomyoma, (6) leiomyoma, (7) granular cell myoblastoma and (8) neurinoma. In the most recently reported series, IG the commonest benign tumor was the adenoma. This type of lesion may at times become cystic and thereby be classified as a cystadenoma; there may also be a proliferation of muscle fibers between the glands thatjustifies the diagnosis of adenomyoma. In the earlier report of Dowdy and his colleagues,15 papilloma was the most frequently encountered benign tumor, being identified in 16 cases. Adenoma was diagnosed in 11 cases, while polyp, fibroadenoma and granular cell myoblastoma were each found in 4 cases. The site of the tumor was the common duct in 11 cases, the ampulla of Vater in 13, and the left hepatic duct, the common hepatic duct and thejunction of the cystic and hepatic ducts in 4 cases each; there were multiple sites in 4 cases. The numerous branched and tubular gland-like structures observed in the walls of the extrahepatic (1)

9

bile ducts and lined with tall columnar cells are thought to be the source from which both benign and malignant adenomatous extrahepatic bile duct tumors originate. 17 Papillomas are usually no more than 2 cm in diameter. Microscopically, they are composed of a connective tissue core covered with tall columnar epithelium. Chu 14 described the fibroma as showing fibrocytes arranged in interlacing bundles with an overall concentric pattern. The granular cell myoblastoma found most frequently in the tongue is characterized by cells filled with eosinophilic granules. Cells resembling young muscle cells are said to have grown on cultures of cells from the tumor. Whisnant and his associates lH gave an account of a 14-year-old boy with intermittent biliary obstruction due to a granular cell tumor of the common bile duct; the tumor was excised and a choledochoduodenostomy was performed. The boy also had multiple superficial neurofibromas. The use of special stains on the tumor gave results supporting the authors' contention that granular cell tumors are of neurogenic origin and can be labeled schwannomas. CLINICAL PRESENTATION

The average age of these patients was 51 years; most of the tumors occurred in patients between the ages of 30 and 76 years, with an equal distribution between the sexes. •Jaundice (either persistent or intermittent), pain, dyspepsia and weight loss have been the most typical symptoms. Chills and fever, indicative of cholangitis, have been common; hemobilia occurred in four patients, with a fatal outcome in one. However, a number of patients were asymptomatic and the tumors were identified only at autopsy. In the series of Dowdy et al.,t5 the onset of symptoms varied from a few days to 35 years before diagnosis. The onset of the disease was generally insidious and followed by a slow progression ofsymptoms. . On physical examination, the liver was frequently found to be enlarged; when the tumor arose below the junction of the cystic and common ducts, the gallbladder was enlarged and palpable. Only on rare occasions were these tumors large enough to be palpable through the abdominal wall. DIAGNOSTIC PROCEDURES

Unless the jaundice is intermittent, oral and intravenous cholecystograms are of no value. Visualization of the bile ducts and the tumor by means of a percutaneous cholangiogram has been described lG and endoscopic retrograde cholangiography would 10

also seem to be helpful if the papilla can be cannulated. Without utilizing such specific diagnostic aids, none of these tumors could have been diagnosed in the past before surgery. The symptoms are not specific and have usually been confused with a malignant obstruction or choledochal lithiasis. Indeed, it may even be difficult to locate and diagnose these benign tumors during an operation. TREATMENT

These patients are operated on to determine the cause of an extrahepatic biliary obstruction. Complete operative radiographic visualization of the biliary system is essential before starting the ductal exploration. The tumors are quite soft, and many authors have emphasized the fact that a probe could be passed without obstruction through the area of the tumor. Iii Although the use of choledochoscopy has not been reported, it would greatly assist in locating such tumors and ensuring their complete removal. Once the tumor has been located and its benign nature determined by examination of a frozen histologic section, a local surgical procedure has usually been carried out, rather than a more radical pancreaticoduodenectomy. In some cases, it may be impossible to preserve the continuity of the bile ducts, and either a cholecystojejunostomy or cholecystoduodenostomy or a choledochojejunostomy or choledochoduodenostomy may be necessary. Dowdy et al. lii summarized the treatment and results of the cases in their review as follows: As noted in Table 1, there were 5 recurrences and 4 postoperative deaths among the 37 patients. Two of the recurrences were in the same patient and may have represented new tumors. In another patient, a fibroadenoma recurred 2 years after one ,vas removed from the left hepatic duct. A cystadenoma of the common hepatic duct recurred in 1 patient and a papilloma of the common hepatic duct in another a year following removal. Only 1 patient with a recurrent lesion died of the tumgr; a second operaTABLE I.-RESULTS OF 40 OPERATIONS ON 37 PATIENTS" OPERATION

Local excision of tumor Local resection and anastomosis Radical resection Total

NO.

RECURRENCES (%)

DEATHS (%)

23

4(18)

2(9)

12 5 40

0(0) 1(20) 5(12)

0(0) 2(40) 4(10)

"From Dowdy and associates. l • 11

tion successfully eradicated the tumor in the other 3 patients. For all of these recurrent tumors, there was some question regarding the possibility that the second tumor may have been new rather than recurrent. Hossack and Herron 16 stated that the prognosis for single lesions is becoming better with improved methods of operating on the biliary tract, and they cited the case of a patient who survived for 13 years after a local excision. However, the prognosis for the patient with multiple tumors is poor. Madden and Smithl!' presented a case of multiple papillomas involving the entire biliary system. The area of initial involvement, the midportion of the common bile duct, was resected and a choledochoduodenostomy performed. Recurrence in the left hepatic duct was treated by a left lobar hepatectomy. Subsequent recurrence in the right ductal system was treated with curettement and intubation. After showing a definite improvement as a result of chemotherapy, cholangitis developed and the patient died of septic shock. The two most essential objectives in treating benign tumors of the bile ducts-relief of obstruction and complete excision of the tumor-can usually be accomplished by local excision, with or without biliary enteric anastomosis.1 5 MALIGNANT EXTRAHEPATIC BILE DUCT TUMORS INCIDENCE

All authors agree that tumors of the biliary tract are rare, although the well-known difficulties of establishing both a macroscopic and a microscopic diagnosis may result in certain of these cases being misdiagnosed at operation. As Sako et al lo have indicated, the incidence of carcinoma of the extrahepatic bile ducts may be expressed as (1) the percent found at autopsy, (2) the percent in biliary tract operations, (3) the percent of all admissions and (4) the percent of all malignant neoplasms. A review of 12 autopsy series published in 1957 10 disclosed a variation of incidence from 0.012% to 0.458%. The incidence in the larger autopsy series varied from 0.012% to 0.047%. Neibling and his colleagues!' reported 41 cases out of 14,000 biliary tract operations at the Mayo Clinic from 1937 to 1946, an incidence of 0.3%. More recently, Kuwayti and associatesH described 63 cases from the necropsy records of the Mayo Clinic in the 39-year period extending from 1915 to 1953. These 63 cases were gleaned from a total of24,029 autopsy records, an incidence of 0.26%. Goldenberg20 noted an incidence of 1.8% in biliary tract operations performed during a 24-year period. The incidence of carcinoma of the extrahepatic biliary tract has 12

been reported as 0.007 - 0.041% of all hospital admissions.!! These lesions are more common in men than in women by a ratio of3:2. According to figures recently published 21 from the National Cancer Institute's third national cancer survey, there were an estimated 11 ,800 new cases of cancer of the liver and biliary passages in 1976. In a U.S. government vital statistics report for 1959,22 malignant lesions of the biliary passages accounted for 4,276 deaths, representing 74% of deaths attributed to primary malignant lesions of the liver and biliary passages. If one considered 40% of the anticipated new cases of liver and bile passage malignant neoplasms in the United States during 1976 to be carcinomas of the bile ducts, this would mean that approximately 4,500 new cases of bile duct carcinoma will occur in this country during the present year, an incidence comparable to that anticipated for new cases ofcarcinoma of the tongue. Bile duct carcinoma, when accurately diagnosed, may not be quite as rare a malignant lesion as it has previously been thought to be. ANATOMICAL CONSIDERATIONS The anatomical relationships of hepatic ducts, hepatic arteries and portal veins in the immediate extraparenchymal hilar region were studied in detail by McArthur et alP They noted that a 3-cm section of the left hepatic duct is generally present between. the site where the duct is formed by the confluence of its two major branches and the place where it joins the right hepatic duct. The extraparenchymal right hepatic duct is usually less than 1.cm in length. The left and right hepatic ducts usually unite at an 80- to 90-degree angle high in the liver hilus, where they are invested in a dense fibrous tissue that completely obscures them from view. The biliary system below the hepatic duct confluence and its related blood vessels abound with anatomical variations. Many years ago, Cole24 commented, "In no region of the body are anomalies so common as in the bile ducts and adjacent blood vessels. It is, therefore, impossible to present any pattern as the 'normal'; a composite of specimens least abnormal becomes the substitute for normal anatomy in this area." After the right and left hepatic ducts unite, the common hepatic duct extends down the hepatoduodenalligament near its right margin. The common hepatic duct varies in length from 1 to 10 em (averaging about 3.5 cm), depending on the level at which it is joined by the cystic duct. The cystic duct, a continuation of the gallbladder, has been described as following one of three general patterns in its confluence with the hepatic duct25 ; (1) the angular type, seen in 64% of cases, joining the right side of the common hepatic duct; (2) the parallel type, seen in 23% of cases, with the 13

Fig 1.-Anatomical relationship of bile duct, hepatic artery and portal vein in region of confluence of hepatic ducts. Note intimate relationship of portal vein and hepatic artery to common hepatic duct.

hepatic duct union deep behind the duodenum; and (3) the spiral type, with the cystic duct passing posterior to the hepatic duct and joining the left side of the hepatic duet in 13% of cases. The common bile duet (that portion of the ductal system from the confluence of the cystic and hepatic ducts down to the duct orifice in the duodenum) varies in length from 4 to 10 em, averaging 6-7 em. 26 It is divided into four parts. The supraduodenal segment is about 3.5 em long and descends along the right margin of the hepatoduodenal ligament. The retroduodenal, or second, portion of the duct descends behind the first part of the duodenum anterior to the vena cava and to the right of the portal vein. The pancreatic, or third, part of the duct passes through the head of the pancreas to the wall of the duodenum. The duodenal (fourth) porFig 2.-Cross section of hepatoduodenalligament, indicating involvement of hepatic artery and portal vein by small, localized bile duct carcinoma.

14

tion extends obliquely through the wall of the duodenum and is surrounded by a complex sphincteric structure. The intimate relationships among the principal structures of the hepatoduodenal ligament-the common bile duct anteriorly and to the right, the hepatic artery anteriorly and to the left (the right hepatic artery in approximately 10% of cases arises from the superior mesenteric artery and passes up the hepatoduodenalligament to the right and posterior to the duct) and the portal vein in a central posterior position-are contributory factors in the inoperability of many of the small bile duct carcinomas (Fig 1). For, although the tumor may be quite well localized, it may involve the hepatic inflow blood supply (Le., the hepatic artery and portal vein) early in its development, thereby making total excision hazardous, if not completely impossible (Fig 2). ETIOLOGY

Although the etiology of bile duct carcinoma remains unknown, many authors (beginning with W. J. Mayo:; in 1903) have speculated on the importance of gallstones as a possible etiologic factor. However, the relationship of gallstones to bile duct cancer has always been far less impressive than the relatively high incidence of gallstones in carcinoma of the gallbladder. For example, .Jones21 reported gallstones to coexist with gallbladder carcinomas in 64.8-88% of the patients in the series he reviewed, while Stewart and associates1 reported an incidence of 20.2% for patients with bile duct carcinoma who also had gallstones. Neibling and his co-workers!l found a high incidence of 57%. In the 416 cases of bile duet cancer collected by Sako and colleagues,1O 161 (38.7%) had stones, either in the gallbladder or bile duets; they pointed out that, according to a previous study, the incidence of gallstones found at autopsy in a similar age group was roughly the same (27.4% for men and 38.5% for women). Of the 103 patients described by Ross, Braasch and Warren,12 21 had calculi in the gallbladder at the time of onset of the symptoms referable to the carcinoma of the bile duct. An additional 14 patients had undergone cholecystectomy at least 3 years earlier; gallstones were definitely identified in 10 cases. Thus, in their series, at least 31 of the 103 patients were known to have had gallstones. When queried, two thirds of our patients replied that they had no previous history of biliary tract disease; one third had a history of previous cholecystitis, cholelithiasis or "trouble with the bile duct." Thus, although it seems clear that gallstones are present in about one third of the patients with bile duct carcinoma (this coexistence seems as closely related in our country as any of the other possible etiologic factors thus far suggested), a caus15

ative mechanism has not been established and, for the time l"~ing, the relationship must be considered interesting but of unknown significance. In a more detailed report on the patients from the Lahey Clinic with bile duct carcinoma and ulcerative colitis, Ross and Braasch2H described an additional 8 patients, bringing the total number of cases with the two associated diseases to 39. Inasmuch as none of their patients had a history suggestive of cholangitis, they considered that biliary tract inflammation could not be considered a causative factor. The bile duct carcinoma developed some years after coloproctectomy in certain patients, leading them to discount any particular influence of the diseased colon per se or the possibility of any increased infection being brought to the liver and biliary system via an abnormally contaminated portal system. Roberts-Thompson and his colleagues2!J found 4 patients with bile duct carcinoma and ulcerative colitis during a 14-year period in their hospital and reported that the incidence of ulcerative colitis in the 29 patients with bile duct carcinoma was 14%, whereas bile duct carcinoma occurred in 1.4% of the inpatients with ulcerative colitis. They considered that bile duct cancer was significantly and consequentially associated with ulcerative colitis but that the nature of the association was unclear. On the contrary, they found no association between ulcerative colitis and carcinoma of the gallbladder. Inasmuch as all of their patients had had ulcerative colitis for 15-25 years before the bile duct carcinoma was recognized, they suggested that the duration ofthe disease was relevant but that the bile duct carcinoma\vas independent of the extent or the severity of the ulcerative colitis. One patient had the entire colon removed 15 years prior to the development of the bile duct cancer. Although there was no history of previous biliary inflammation, 2 of their 4 patients had undergone cholecystectomy. Undoubtedly closely related to the etiology of extrahepatic bile duct carcinoma is the very striking association of Clonorchis sinensis hepatic infections with intrahepatic cholangiocarcinoma, as described by BelamariclO in patients coming from Hong Kong. In 19 patients with cholangiocarcinoma, 18 (94%) had adenomatous hyperplasia and duct wall fibrosis characteristic of severe clonorchiasis. Similar changes were found in only a third of the control patients. None of the patients had cirrhosis. Belamaric believes that the nearly constant presence of severe clonorchiasis in patients with intrahepatic bile duct cancer, the close physical relationship of the main tumor mass to infected ducts and the frequent coexistence in the same duct of focally atypical epithelial hyperplasia and invasive cancer, as well as the results of animal experiments, all support a cause-and-effect relationship. The 16

tumors he describes are usually located deep in the substance of the liver close to a parasitized duct, but sometimes the tumor occupies a suprahilar position involving the larger hilar bile ducts. The report of Gallagher et al.31 also emphasizes the role of infection and irritation in the presence of bile as a possible causative factor in the production of bile duct cancer. They have reported 2 cases with congenital dilatation of the intrahepatic ducts with clinically undetected cholangiocarcinoma. Ofthe 25 similar cases with congenital duct dilatation that they reviewed in the literature,2 additional carcinomas appeared: one was hepatocellular, the other cholangiocellular. They also found 3 intrahepatic and 8 extrahepatic bile duct carcinomas in a review of 400 cases of congenital choledochal cyst. They believe it interesting that there have been no cases of carcinoma of the bile ducts reported with other hepatic congenital anomalies such as polycystic disease or congenital hepatic fibrosis, and they conclude by stating, "Any condition in which bile duct epithelium is exposed to slow flowing bile for long periods is likely to predispose to cholangiocarcinoma." A number of other possible causative factors have been proposed from time to time without confirmation, such as the evolution of a benign glandular papilloma, carcinogenic action of cholic acid in the susceptible subject or the conversion of bile acids to methylcholanthrene. The common factors in three of these possible etiologic conditions-gallstones, parasitic infections and congenital dilatations - are: (1) the slowing of the flow of bile, (2) the presence of infection and (3) the probable inflammatory reaction in the duct wall. Although the presence of clinical cholangitis has not been found in many of the patients with bile duct carcinoma and ulcerative colitis, clinically significant cholangitis does occur in some of these patients: some have had cholecystectomies (probably for lithiasis); in others, the pathologic changes of sclerosing cholangitis occur in the duct wall. So, once again, an inflammatory reaction may be present in the duct wall that, when combined with the presence of bile, may create an appropriate environment for the development of a malignant tumor. PATHOLOGY

On the basis of their gross characteristics, malignant neoplasms of the bile ducts can be divided into three types: (1) local, or nodular, (2) diffuse and (3) papillary. The local tumors have been described as being approximately 2 cm in diameter and consisting usually of an annular, constricting, grayish white lesion, rarely with an ulcerated interior. The duct is distended above the tumor and collapsed distal to it. The 17

Fig 3.-Photomicrographs of adenocarcinoma of bile duct from 2 cases. A, Case 1. Dilated hepatic duct contains inspissated bile; epithelial lining is lost". Surrounding duct are many irregular glandular spaces. separated by fibrous stroma. which is variably infiltrated by chronic inflammatory cells. Fragments of liver parenchyma are visible at margins. Hematoxylin-eosin; x10. B, Case 2. Dilated bile duct lumen (top) is lined by columnar cells that dip into under-

18

diffuse growths produce extensive thickening of the entire duct wall, with resultant constriction of the lumen. The duct is converted into a firm, rigid tube that is easily confused with sclerosing cholangitis, as Altemeier et ai. 1I have pointed out, or into a benign stricture. A single prominent tumor mass that would offer an appropriate site from which a biopsy specimen might be taken may not be present. Depending on the primary site of the tumor and its size, any of these tumors may extend from the hilus into the liver parenchyma. It is particularly important for the surgeon to be aware of the gross characteristics of these tumors, inasmuch as histologic confirmation from a biopsy specimen of the duct wall may well be misleading. The diffuse tumor, minus a specific tumor nodule but exhibiting a generalized, dense, fibrotic thickening of the duct wall, may be particularly confusing. The nodular tumor at the confluence of the right and left hepatic ducts may be so small and so well protected in the hilus that it may not even be palpable unless the area is widely dissected. The surgeon is naturally reluctant to take a large segment of the duct wall for a biopsy specimen, but an inadequate specimen adds to the difficulties of making a proper histologic diagnosis. The papillary tumor that projects into the lumen of the duct is usually readily identified when the thickened duct is opened. Such a tumor frequently involves multiple areas of the duct mucosa and may be quite extensive. Stewart et aP considered the gross characteristics of 104 reported tumors. Of the 35 tumors that involved the hepatic ducts, 75% were considered local and 25% diffuse; 56.3% of the 48 tumors at the confluence of the hepatic ducts were local, and 43.7% were diffuse. In the common bile duct, 57% of the 21 tumors \vere local, and 43% were diffuse. On histologic examination, these tumors were allfound to be various types of adenocarcinomas; in general, the histologic type correlated with the gross characteristics of the tumor. The grossly nodular tumors revealed the histologic characteristics of an adenocarcinoma, ranging from poorly differentiated to well differentiated. Histologically, the diffusely fibrotic tumor will show a dense sclerotic or fibrotic adenocarcinoma (Fig 3), and the grossly papillary tumors will be identifiable as papillary adenocarcinomas. Ingis and Farmer32 noted a major difference in the pathologic features of tumors located in the hepatic ducts, as compared to those arising in the common duct. Of their 14 cases of hepatic lying connective tissue, forming irregular gland spaces that have excited a desmoplastic reaction. Hematoxylin-eosin x50. (photomicrographs courtesy of Walter Coulson, M.D., Department of Pathology, University of California. Los Angeles, School of Medicine.)

19

TABLE 2.-CLINICAL SYNDRQ;\IES OF CARCINQ;\IA OF THE BILE DUCTS" Distal duct periampullary tumor Cystic duct obstruction Acute cholecystitis Simple bile duct obstruction Single hepatic duct obstruction Intrahepatic duct obstruction "From Braasch. 33

duct carcinoma, 5 were scirrhous adenocarcinomas, 2 were adenocarcinomas with fibrous reaction, 6 were poorly to well-differentiated adenocarcinomas; and 1 was a papillary adenocarcinoma. Of the 9 common bile duct lesions, only 1 was a scirrhous carcinoma; 7 were adenocarcinomas of varying grades of differentiation, and 1 was diagnosed as anaplastic adenocarcinoma. These tumors metastasize to the liver and to regional lymph nodes in the hepatoduodenalligament. Kuwayti et ai.H reported metastasis or direct spread in 71.4% of their 63 cases. Extension or metastasis to the liver, lymph nodes, pancreas, gastrohepatic omentum or mediastinum occurred in 48.5-52.3% of the cases reported by Stewart et al.,7 depending on the site of origin. Frequent invasion of the regional nerve plexuses has also been noted. Tumors arising at or above the confluence of the hepatic ducts tend to extend into the parenchyma of the liver. Tumors of the common hepatic and suprapancreatic common ducts extend to involve the hepatic artery and portal vein, and those of the lower duct extend into the pancreas and duodenum. Braasch33 contends that neither the microscopic nor the macroscopic classification of bile duct neoplasms is particularly helpful in the management of a given clinical case. He prefers a classification on the basis of the . divergent clinical syndromes that these tumors may present, as outlined in Table 2. CLINICAL COURSE

AGE AND SEX. - The average age of patients in the series of Stewart et aU was 59.3 years. Of the patients described by Kuwayti and associates,S 71.4% were in the sixth and seventh decades of life, the average ages being 62.2 years for men and 60.7 years for women. Although the sex ratio has varied between these series, it has generally been about 3 men to 2 women. Kuwayti et ai.s reported 46 men and 17 women, a ratio of 2.7: 1. In the series of Stewart and his colleagues,; the ratio was 73 :31. In a 20

report by Ross et al.,12 there were 59 men and 44 women; the median age for men was 55 years, with a range from 23 to 76, while for women it was 57 years, with a range from 34 to 78. They commented that most reports comprise too few patients for a valid determination of the age and sex distribution, but a wide age range with a peak incidence in the sixth decade has been noted in several series. In our report l3 of 63 patients, the age range was 24 -78 years, with a distribution as indicated in Figure 4; there were 36 male and 27 female patients. SIGNS AND SYMPTOMS. - The principal signs and symptoms are those of an obstructive jaundice, but there are unfortunately no unique clinical features that will specifically identify the disease as being due to a malignant bile duct tumor. Sako et al. to described jaundice in 90% of their patients, usually occurring within 4 months before admission and becoming progressively more severe. Pain occurred in approximately half of the cases. Ross and his associates 12 noted that, for 40 patients, a mild postprandial epigastric discomfort was first experienced approximately 2 months before the onset of jaundice. Moreover, pain in the lower part of the chest (3 patients), backache (3 patients), and severe pain in the right upper quadrant of the chest, suggestive of biliary colic (10 patients), were also noted. Often, the severe, persistent pruritus is the most distressing symptom for the patient; at times it has preceded the onset of jaundice, but it i~ more comFig 4.-Age distribution of 63 cases. More than half the patients were 50-70 years old. (From Longmire, W. P., Jr., McArthur, M. S., Bastounis, E. A., and Hiatt J.: Ann. Surg. 178:333, 1973.)

20

5

o

20

30

40

50 AGE, yr

60

70

80 21

mon and severe in the later stages of the illness. Anorexia and weight loss generally appear together as the disease progresses. Nausea and vomiting occurred in 15 of the 104 cases of Stewart et aU Signs and symptoms of cholangitis (e.g., chills and fever) are rare until the biliary tract has been surgically transgressed but are common thereafter. As the illness progresses, loss of strength is a frequent complaint. Less usual symptoms are constipation, diarrhea, a sense of weight or pressure in the abdomen, flatulence and belching. In the carefully evaluated series of Kuwayti et aZ.,8 the major initial signs and symptoms relative to the illness of their 63 patients were as follows: jaundice, 96.8%; loss of weight, 95%; pruritus, 88.5%; anorexia, 74%; dark urine, 63%; clay-colored stools, 62%; abdominal pain, 57%; weakness, 44.5%; fever, 14%; diarrhea, 13%; and chills, 9%. Contrary to information found in other series, a gradual onset of jaundice was noted in more than 50 of the 63 patients in the UCLA Hospital series; indeed, only 3 patients were aware of an acute onset of their symptoms. Pain, present in one third (21) of the patients was the second most-noted symptom, with weight loss, decreased appetite and general malaise recorded in fewer than one fourth of the patients. Evidence of cholangitis was recorded in only 7 of the 63 patients; the symptoms seemed to be similar, regardless, of the anatomical location of the carcinoma. There was no significant difference in the mode of onset or the predominant symptoms of lesions of the proximal, middle or distal third of the extrahepatic biliary system. Approximately half (33) of the patients consulted a physician within the first 3 months after onset of symptoms, and about half (32) received some definitive treatment within 4 months. Ross and associates l2 commented that in their series abnormal physical signs were few. Progressive hepatomegaly was noted in the mrUority of patients who had a prolonged survival period, but it was usually not observed when the patient was first seen. Evidence of portal hypertension was apparent clinically or at operation in 14 patients who were in the later stages of the disease. The liver was palpable 2-4 fingerbreadths below the right costal margin in 84% of the patients reported by Kuwayti et aZ.;s it was generally not tender to deep palpation and only rarely nodular. The gallbladder was clinically palpable in 31.5% of the patients who had not undergone cholecystectomy. Nine of the 18 patients with a palpable gallbladder also had stones. A palpable abdominal mass representing the primary bile duct tumor has not been mentioned in any of the recently reported series. Some degree of abdominal tenderness was present in 26 cases reported by Stewart and his colleagues,7 and 3 had associated rigidity. Late signs included abdominal distention (11 cases); evidence of ascites (8 cases) and an enlarged, tender spleen (3 cases). 22

LABORATORY STUDIES.- Varying degrees of anemia have been typical. In our cases, the hematocrit reading was less than 40%, and the white blood cell count was more than B,OOO/cu mm for half of the patients. However, slight to moderate anemia and a normal to moderately increased polymorphonuclear leukocyte count have been of little diagnostic value. Other pertinent laboratory studies revealed nonspecific evidence of extrahepatic biliary obstruction with secondary liver damage. Ross et al. 12 reported a serum bilirubin level of more than 15 mg/100 ml for more than half of the patients when first seen at the Lahey Clinic (most of them had been examined previously at another hospital). The serum alkaline phosphatase levels of the patients were also significantlyelevated. SPECIAL DIAGNOSTIC TESTS CHOLANGIOGRAPHY.-In the face of a markedly elevated serum bilirubin level, the usual oral and intravenous cholangiograms are of no value and, if performed, represent an unnecessary expense for the patient or his sponsor. The most definitive diagn9stic test (even more reliable in certain cases, I believe, than operative biopsy) is the percutaneous transhepatic cholangiogram (PTC). Others,n consider that such procedures as percutaneous transhepatic cholangiography and retrograde fiberoptic cholangiography have limited usefulness since the indications for surgical exploration are already so clear-cut. In our previous report,13 pertinent information was obtained for each of the 12 patients on whom percutaneous transhepatic cholangiography\vas performed successfully. Percutaneous cholangiograms, performed with the-use of the technique introduced by Okuda and associates,31 have recently been successful in demonstrating the intrahepatic biliary system in 100% of our patients whose ducts were obstructed and in 60% of those patients with a nonobstructed intrahepatic biliary system (Fig 5). * Redeker et a1.3~ have previously reported similar results with this technique, utilizing the "Chiba needle." Intrahepatic ducts were entered and adequately opacified in 32 (BO%) of their 40 patients and were successfully entered in all 20 cases of proven biliary tract obstruction. Nondilated bile ducts were entered in 12 (60%) of 20 instances. Okuda and associates 31 consider the major technical advances of their procedure to be (1) entry from the lateral chest wall, which provides better protection against bile leakage because of the thickness of the liver tissue "These procedures have been performed by Leonard I. Goldstein, M.D., Division of Gastroenterology, Department of Medicine, University of California, Los Angeles, School of Medicine.

23

Fig 5.-Percutaneous cholangiogram demonstrating obstruction of common hepatic duct by papillary intraductal tumor.

through which the needle passes; (2) use of the thinnest needle possible without a catheter sheath; (3) the searching for intrahepatic bile ducts by injecting the contrast medium instead of attempting to aspirate bile. Prophylactic antibiotics are given for 2 days before and 3 days after the procedure. The percentages of successful examinations are given in Table 3. The authors made a particular note that the procedure was successful in 13 of 20 patients with intrahepatic cholestasis, a condition that is otherwise very difficult to differentiate from extrahepatic obstruction wi thout surgical exploration and that may be aggravated by an anesthetic and an operation. The complications they encountered are listed in Table 4. 24

TABLE 3.-SUCCESS RATE OF PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY IN DIFFERENT DISEASE GROUPS'" GROUP

NO. OF PATIENTS

NO. OF SUCCESSES

Malignancy of liver, bile, duct and pancreas Cholelithiasis Other surgical diseases Nonsurgical diseases Total

95 121 18 80 314

95 104 15 54 268

SUCCESS RATE, %

100.0 85.9 83.3 67.5 85.3

"From Okuda and associates."

Operation for bile leakage was required for one patient with carcinoma of the bile duct 8 hours after the examination. An operation was not necessary for two patients who had intraperitoneal bleeding. On the other hand, early operation was necessary in 2 of the 40 cases reported by Redeker et a[.3" (in one case, for bile peritonitis in a patient with complete biliary obstruction due to pancreatic carcinoma). In the other patient, exploration was performed because of increasing fever and chills; although no bile leak was found, the presence of carcinoma of the papilla of Vater, visualized on the cholangiogram, was confirmed. In our 35 cases, we have noted one case of transient bacteremia and one questionable intraperitoneal bleed, neither of which necessitated early operation. The demonstration of a dilated ductal system above a constricting obstructing lesion without filling defects in a patient who has not previously had upper abdominal surgery is diagnostic of a neoplastic obstruction. In a North American patient, if the lesion TABLE 4.-COMPLICATIONS OF PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY"

C011PLlCATION

NO. OF PATIENTS

% OF TOTAL GROUP (314 PATIENTS)

NO. (%) AMONG NONSURGICAL CASES (80 PATIENTS)

Fevert Blood pressure, 25 cm Hg Bile leakage Bile peritonitis Bleeding Cough:j: Total

11 6 3 2 2 1 25

3.5 1.9 0.95 0.64 0.64 0.32 7.96

0(0) 0(0) 0(0) 0(0) 0(0) 1(1.25) 1(1.25)

"From Okuda and associates." tTemperature > 38 C. :j:Preexisting disease.

25

is in the common hepatic duct or above, it will almost certainly be a bile duct carcinoma. CHOLEDOCHOPANCREATOGRAPHY. - The endoscopic retrograde choledochopancreatography (ERCP) is another recently available diagnostic technique that will assist in establishing a definitive diagnosis in certain cases of obstructive jaundice. After the introduction of the fiberoptic gastroscopy by Hirschowitz et al.3H in 1958 and the demonstration of pancreatic duct cannulation by Rabinov and Simon37 in 1965, the first endoscopic cannulation and roentgenologic visualization of the pancreatic duct were achieved by McCune and associates:lS in 1968. With certain technical refinements of the instrument and the technique, contributed particularly by ,Japanese endoscopists,:l!/· ~o it has become possible for the skilled endoscopist to cannulate the papilla of Vater and to visualize radiographically the bile ducts or pancreatic duct or both in 75- 96% of cases. Blumgart~1 states that ERCP has the advantages of being useful early in a patient's illness; it has few hazards, it can provide an unequivocal preoperative diagnosis for as many as 80% ofjaundiced patients, and it may be particularly valuable in demonstrating a patient's normal biliary ductal system in some cases. In a series of 146 cases ofjaundice evaluated by ERCP, he found 22 in which there was no obstruction of the biliary ductal system. Our plan of investigation for the jaundiced patient is similar to that described by Blumgart.~1 We first perform a full range ofliver function tests including, when indicated, liver biopsy, upper gastrointestinal x-ray studies and, in patients with a .serum bilirubin value of less than 3 mg/lOO ml, intravenou~ cholangiography with tomography. If the cause of the jaundice remains uncertain, ERCP is used unless contraindicated by Australian antigenemia, cholangitis or recent pancreatitis. If cannulation of the papilla is unsuccessful or if the ductal system cannot be adequately visualized, a percutaneous transhepatic cholangiogram is considered. In Blumgart's series of 146 patients, duodenoscopy was successfully performed in 144, the papilla of Vater was located in 140, and the ampulla was cannulated in 114. In 3 patients, cannulation was not attempted, inasmuch as carcinoma of the papilla of Vater was diagnosed endoscopically. A definitive diagnosis was established in 109 patients, and useful information was obtained in an additional 11 patients. However, misleading information was obtained in 1 patient, and endoscopy failed to be helpful in 24. OTHER DIAGNOSTIC PROCEDURES. - Two procedures for liver scanning with radioactive materials have been utilized for diagnostic examinations on patients with jaundice. The most commonly used isotope for liver scanning today is !J!lffiTc-sulfur colloid, a ra26

dionuclide of technetium that is cleared from the blood by the phagocytic reticuloendothelial (Kupffer) cells in the liver and that is used primarily to detect space-occupying lesions in the liver. If the ductal system is widely dilated, this scan will demonstrate a somewhat nonspecific diffuse defect or "cold area" at the hilus of the liver. Liver scans with the use of ~:JmTc-sulfur colloid were done on 11 ofour patients. 13 The findings were abnormal but not diagnostic for 7 patients and were normal for 4. Ingis and Farmer32 used liver scans on 4 patients; the scans showed diffuse replacement disease in 3 patients and both splenomegaly and hepatomegaly in 1. The test has little value in the diagnosis of obstructive jaundice other than to rule out primary or secondary hepatic tumor. The injection of 13lI-rose bengal, which is concentrated by the hepatic cells and cleared in the bile, has been proposed as a test to evaluate the degree and the site ofbiliary obstruction. 42 However, the original reports of an approximately 98% accuracy have not been substantiated by others. Olsson and Bjurstam43 performed the test on 23 patients with decreasing, 4 patients with unchanged and 19 patients with increasing serum bilirubin concentrations. In the latter two groups, a correct diagnosis of the obstruction site was obtained in only 53%, considered to be too Iowa percent to justify accepting the test for routine clinical use. After a few preliminary trials, we no longer included the test in our diagnostic evaluation of possible obstructive jaundice. Celiac and superior mesenteric angiograms were obtained for 2 patients in the series reported by Ingis and Farmer;32 encasement of the right hepatic artery was demonstrated in 1 case. Bree and Reuter4~ studied the hepatic angiograms of 10 patients withimpacted common duct stones to determine the effects ofobstructive jaundice and found angiographic evidence of increased hepatic artery blood flow in all of them. In 2 cases, rounded lucent areas were misdiagnosed as hepatic metastases, with a resultant delay in operation. They believed that the alteration in hepatic blood flow was caused by an increased resistance to blood flow in terminal portal vein radicals compressed by distended bile ducts. In our previously reported series,13 findings from arteriograms were abnormal but not diagnostic for 3 patients and were negative for 2. We rarely use selective arteriography today when evaluating cases of obstructive jaundice. Cytologic examination of duodenal contents is also infrequently used today, probably because more helpful and reliable diagnostic tests, such as ERCP and PTC, have become so widely available. However, some 15 years ago, Raskin et al. 45 and Dreiling et al. 46 recorded very satisfactory results in the diagnosis of pancreatic and biliary tract cancer by utilizing a combined secretory exfoliative cytologic test of duodenal aspirations. 27

In reporting on the value of ultrasonography in the investigation of obstructive jaundice, Taylor and Carpenter17 described their technique of moving the transducer through an arc under the right costal margin, which enabled them to make accurate diagnoses in two jaundiced patients. In one, there were multiple defects owing to tumor metastases (lesions less than 5 mm in diameter were said to be resolved separately); in the other, the distended gallbladder and grossly dilated, obstructed biliary ducts were correctly identified. Continued technical improvements are increasing the detail of the ultrasonographic image and enhancing the diagnostic accuracy of the procedure. We are now using ultrasonography in the diagnostic assessment of an increasing number ofjaundiced patients. The value of the total body scanner in identifying lesions ofthe biliary tract has not been adequately evaluated as yet, but it may offer still another diagnostic aid. TREATMENT PREOPERATIVE PREPARATION. -As previously indicated, the majority of our patients have a history of gradually increasing jaundice, loss of appetite, fatigue and weight loss, but they are not acutely ill. The serum bilirubin and serum alkaline phosphatase levels are markedly elevated; liver enzyme concentrations, however, are relatively normal, as are serum electrolyte levels. Signs of cholangitis (e.g., chills, fever and leukocytosis) are infrequentlyencountered. Severe chronic jaundice may be associated with depression of the prothrombin time. As the diagnostic evaluation proceeds, fluid and electrolyte deficiencies, if any, are corrected; a reduction of prothrombin time to less than 40% of the normal value is treated with subcutaneous injection of phytonadione AquaMephyton or another soluble vitamin K preparation, and blood is matched for possible transfusion. Mild temperature elevations and leukocytosis will usually respond to restriction of activities and diet, with or without the administration of an antibiotic such as ampicillin. Established infection with marked jaundice, chills, fever and leukocytosis is difficult to control completely until the biliary obstruction is relieved. If a brief period (48 hours) of treatment-consisting of limited oral intake, intravenous administration of liquids and antibiotics-does not achieve clinical improvement, or if the patient's condition worsens, surgical relief of the obstruction will be necessary. In such cases, a definitive operation may be performed unless additional signs of gram-negative sepsis, e.g., circulatory collapse and depression of cerebral function, have supervened, in which case mere decompression of the biliary tract is all that is immediately indicated as a lifesaving procedure. We have had no experience 28

with percutaneous transhepatic catheter decompression of the biliary system when the obstruction is due to a malignant tumor,48 but we have generally noted poor return when attempts have been made to aspirate bile, particularly through the "thin needle" currently used for percutaneous transhepatic cholangiography. SURGICAL PROCEDURES. -The identification of bile duct tumors, their surgical treatment and their prognosis are all related to the location of the tumor in the ductal system. We have previously Suggested l3 dividing the extrahepatic biliary tract into three general areas: (1) the upper region, including the left and right hepatic ducts, their confluence and the common hepatic duct; (2) the common duct from the region of the cystic duct to the pancreas and (3) the intrapancreatic portion of the common duct, not including the papilla of Vater. Of our 63 cases, 34 were located in the upper region, 13 in the middle third and 13 in the lower third, or intrahepatic, region; 3 were of the diffuse papillary variety.

Tumors ofthe Hepatic Ducts {Upper-Third Tumors}.-The first problem to be faced during an operation is locating the site of obstruction and identifying the true nature of the lesion. In 17 of23 cases reported by Whelton and associates,4iJ 9 of 13 cases recorded by Klatskin,5° and 8 of our 25 cases, the cause of the biliary obstruction was not identified at the initial operative biliary exploration for obstructive jaundice. In the cases of our other 17 patients undergoing preliminary operations, the presence of a neoplasm was at times suspected but not proved, either because biopsy was not done or because the biopsy specimen did not contain tumor. If the site of the duct obstruction has been localized by preopm"ative studies of the region of the hepatic ducts and their confluence and if the intrahepatic ducts above this area are dilated, the obstructing lesion is almost certainly malignant. I have often been surprised (even with preoperative x-ray films demonstrating the site of obstruction at hand) how elusive a small fibrotic tumor at the confluence of the hepatic ducts high in the hilus may be. It may be difficult both to palpate and to visualize such tumors. If preoperative localization of the obstruction has not been carried out, the first steps in the operation will be to examine carefully the gallbladder, to open the peritoneum over the hepatoduodenal ligament longitudinally and to inspect the common bile duct. With a high obstructing lesion, the common bile duct will be collapsed, and the wall of the duct will frequently appear thickened, either owing to its collapsed state or to infiltration with sclerosing tumor. A cholangiogram should be made, with care being taken (1) to demonstrate free flow of dye distally into the duodenum and equally important (2) to visualize the intrahepatic 29

ducts or to demonstrate with certainty that there is a complete obstruction high in the ductal system (Figs 6-9). After the demonstration of a block in the hepatic ductal system on an x-ray film, either before the operation or early in the procedure, the next step will be to visualize the lesion and to attempt to secure an adequate frozen-section biopsy specimen before proceeding with definitive treatment. Removal of the gallbladder greatly facilitates access to the immediate extraparenchymal hilar area. If the cholangiogram has demonstrated obstruction above the cystic duct, there is no reason to preserve the gallbladder for a possible bypass procedure. Before the removal of the gallbladder and the mobilization of the hilar structure (both anteriorly and posteriorly, so that the area of IWpatic duct confluence can be palpated between the thumb and index finger), it may be difficult to appreciate by palpation the presence of a small tumor in this area. After the obstructing lesion has been localized, an effort should be made by biopsy to establish its malignant nature. Herein lies the second major surgical problem in dealing with this disease, for the removal of a sizable segment of an abnormal duct at biopsy may well leave a defect in the duct wall that is difficult to close, and there is a real danger of creating a biliary fistula. Consequently, the surgeon may be forced to reFig 5.-Drawings indicate importance of demonstrating condition of intrahepatic ductal system. as well as unobstructed flow of dye into duodenum. A, Inadequate operative cholangiogram. Patency of distal duct is demonstrated. but incomplete proximal filling does not show either complete duct obstruction or condition of intrahepatic ductal system. B, Adequate operative cholangiogram, showing dye passing freely into duodenum and complete proximal obstruction or passage of dye above partial obstruction into diffusely dilated intrahepatic ductal system, indicative of neoplastic obstruction. C, Adequate operative cholangiogram. Patency of intra- and extrahepatic ducts demonstrated, showing irregular areas of constriction and dilatation characteristic of sclerosing cholangitis (cholestatic jaundice, cholangiolytic hepatitis). B

30

Fig 7.-0perative T-tube cholangiogram of patient with carcinoma at confluence of left and right hepatic ducts. Note diffuse uniform dilatation of intrahepatic ductal system above neoplastic obstruction.

move such an inadequate specimen that an accurate pathologic diagnosis would be impossible. Here the presumptive x-ray diagnosis of a bile duct carcinoma is greatly reassuring, because the characteristically dilated intrahepatic ductal system indicates that the obstruction is due to tumor that may possibly be excised or bypassed if a defect should be created in the duct wall by biopsy. Once the tumor has been visualized and the biopsy specimen secured, the extent of the tumor must be assessed. Although on first examination one might conclude that the tumor is small and well localized, the area must be adequately dissected to determine (1) whether the tumor has extended into the parenchyma of the liver along with the right or left hepatic duct and (2) whether the tumor involves the hepatic artery or the portal vein or both vessels (see Fig 2). Excision of the tumor in this position with the reestablishment of biliary enteric continuity is a major procedure 31

Fig B.-Operative T-tube cholangiogram of patient with papillary intraluminal bile duct carcinoma of upper third of ductal system. Tumor completely obstructs bile duct.

that should be undertaken only if there seems to be a reasonable chance that the tumor will be completely removed or significantly palliated because the lesion is small, well localized and histologically acellular and fibrotic, suggesting a low growth potential. Overly aggressive attempts at surgical excision may significantly embarrass the hepatic inflow blood supply, Le., the hepatic artery and portal vein. An additional step in the operative evaluation of these cases for possible resection has been the endoscopic examination of the ducts by choledochoscopy, as reported by Tompkins51 and colleagues. They presented five illustrative cases of extrahepatic bile duct obstruction in which choledochoscopic examinations were performed at the time of bile duct exploration, demonstrating widely scattered, multicentric, intraductal tumor growths in patients whose lesions were otherwise considered resectable. It is suggested that this unrecognized diffuse tumor growth may in part account for the poor survival rates after the resection of ap32

Fig 9.-Postoperative T-tube cholangiogram of patient with sclerosing choledochitis. Note irregular filling with areas of constriction and dilatation of intrahepatic ductal system. Patient experienced chronic intermittent obstructive jaundice for 13 years.

parently localized bile duct tumors. It has also been observed that the tumor not only may be multifocal but may also assume various pathologic types within the same ductal system. Invasion of the hepatic parenchyma at the hilus or involvement of the hepatic artery and portal vein in the hepatoduodenalligament made it possible to resect the tumor in only 6 of our 33 patients operated on for tumors in the upper third of the ductal system; in 2 of these cases, major hepatic resections were combined with the local tumor excision. Intrahepatic cholangiojejunostomy was performed eight times. Duct enteric bypass could be carried out in only 3 cases. The most frequently performed procedure was dilatation of the site of obstruction and intubation of the ducts above and below the tumor, usually with a T tube (Fig 10). Terblanche et ai. 52 reported their experience with 21 cases of carcinoma in the upper-third region and described their adaptation ofthe V-tube technique 5 :! for the palliation of malignant biliary obstruction. With the aid of a dilator, one end ofthe V tube is passed through the tumor into the right or left hepatic ductal sys33

Fig 10.- Treatment of tumors of upper third of extrahepatic ductal system. showing tumors at or near confluence of left and right hepatic ducts. A, Dilatation and intubation of obstructing nonresectable tumor with T tUbe. which may extend above tumor into right. left or both hepatic ducts. B, Excision of tumor at hepatic duct confluence with hepaticoenterostomy (hepaticoduodenostomy or hepaticojejunostomy. Roux-en-V).

tern and forced through the liver parenchyma, out the surface of the liver and through a stab wound in the ante~ior abdominal wall. The common bile duct is repaired at the other end, which is also brought to the outside through the abdominal wall (Fig 11). The tube is flushed twice daily, first with dilute kanamycin solution and later with physiologic saline solution. They also reported excellent palliation in one patient with irradiation after T-tube intubation of the tumor. We combined the use of bilateral U tubes with irradiation in one patient who is alive and has demonstrated excellent palliation to date. Postoperative complications in our 16 cases were most frequently related to infection in the ductal system or in the right subhepatic space or wound, to biliary fistulas or to gastrointestinal bleeding. Jaundice was relieved in 15 cases, partial relief was obtained in 9 and no apparent relief resulted in 6. Five patients were alive at the time of our report, four of them from 2 to 7 1/2 months and 0I.1e for 4 11z years after the operation. Tumor excision at this level inevitably resulted in division of the hepatic ducts above the level of their confluence, necessitating anastomosis of both the left and right hepatic ducts (usuall~' to the jejunum) (Fig 10, B). Proximal extension of the tumor followed one or the other of 34

U-tube intubation

Fig 11.-Dilatation of obstructing tumor and intubation of ductal system with long tube passing into intrahepatic ducts through liver and abdominal wall to outside. Distal end of tube may end in biliary system below obstruction or .it may pass out duct and through abdominal wall to outside (U tube). Similarsystem of intubation may be used after excision of tumor and hepaticojejunostomy, with distal end of tube passing into jejunum if there is residual tumor near anastomosis.

the hepatic ducts so that, when the procedure of dilatation and intubation of the obstruction was used, the catheter usually passed into the right or the left ductal system. It has generally been our impression that ifone achieves complete drainage of one half of the liver and if the biliary system ofthe.other half is uninfected, the patient's symptoms will be palliated. Although successful palliation as a result of partial left hepatic lobectomy and intrahepatic cholangiojejunostomy has been reported by others, the procedure was generally ineffective as a palliative bypass in our cases. Two of the eight patients survived for more than 2 years, one for 2lf2 years and the other for 4lf2 years. In none of the eight cases was there free communication between the left and right intrahepatic ductal systems, a condition that we consider to be essential if intrahepatic cholangiojejunostomy is to be successful. In an attempt to perform an en bloc resection of a hepatic duct 35

tumor, a portion of the inflow blood supply was excised and a three-quarter right hepatectomy was performed in one patient (Fig 12). Despite the extensive resection, the patient died of recurrent tumor 11 months after the operation. It is possible that an endoscopic examination of the bile ducts, which we were not doing at that time, would have demonstrated tumor beyond the proposed limits of our operation. The tumor site was not correlated with the operative procedures performed in the series of 102 patients reported by Ross et al. 12 Resection of the tumor was possible for only 12 patients, 3 of whom remained asymptomatic for more than 5 years. A biliary enteric bypass was performed on 19, 11 of whom lived for 2 years or longer. Of the 52 patients treated by dilatation and tube intubation, 11 survived for 2 years or longer. External biliary fistulas in 11 patients were poorly tolerated. In 10 of the 14 cases reported by Ingis and Farmer12 in which the tumor was located in the upper-third region, the obstructing tumor was dilated and the duct was intubated with a T tube. Three patients had hepaticoduodenostomy, one after resection of the cystic and hepatic ducts. Fig 12.- Extensive resection of carcinoma of bile duct with excision of involved portal vein and right hepatic artery, as well as three-quarter hepatic resection. (From Longmire, W. P., Jr., McArthur, M. S., Bastounis, E. A., and Hiatt, J.: Ann. Surg. 178:333, 1973.)

36

Tumors of the Middle Region of the Ductal System. - Eleven of the 77 malignant bile duct tumors reported by Warren et al. 51 were in the common duct above the pancreas. Seven patients were treated by resection and end-to-end anastomosis or hepaticoenterostomy; of these, 6 survived for more than 1 year and 3 for more than 3 years. In 13 of our cases, the tumor was classified as occupying the middle third of the extrahepatic ductal system, i.e., the suprapancreatic portion of the common bile duct. Three of these patients were treated by dilatation of the tumor and T-tube intubation of the duct. Duct enteric bypass was performed in 3 cases. Resection of the tumor and duct enteric bypass were possible in 4 cases, and 3 patients were treated by hepatic resection and cholangiojejunostomy (Fig 13). One of these patients lived for 9 months and one for 2lf2 years. Of our 13 cases, the jaundice was relieved in 11 patients and partially relieved in 2. Palliation was considered excellent in 3, good in 7 and fair in 1. Six patients survived for 3 years or more, 1 for more than 11 years. Ingis and Farmer32 considered all of their 9 common bile duct patients together; 2 underwent Whipple procedures, 1 had a resection and end-to-end anastomosis of the common bile duct, 2 underwent choledochoduodenostomy, 1 underwent resection and hepaticoduodenostomy and 2 had T -tube intubation. The location of these lesions makes them more readily identifiable; however, histologic confirmation of a malignant tumor may still pose problems, particularly in the more scirrhous tumors, in which the obstructing lesion must also be differentiated from a benign stricture or, more frequently, from sclerosing cholangitis. Here, too, the pre- or intraoperative cholangiogram is of vital importance, inasmuch as the characteristic uniform proximal duct dilatation of the malignant obstruction will not be present in cases of sclerosing cholangitis. Resection of the middle-third tumors can be performed in a higher percentage of cases; although the rate of cure does not seem to be altered, the period of survival is significantly better than for the lesions of the upper third. Distal Third Lesions. - Tumors that are located in the intrapancreatic portion of the common duct are generally grouped clinically with the periampullary tumors. Differentiation of the tumor from the far more common carcinoma of the pancreas may be difficult at operation. However, because of their site of origin, these tumors produce jaundice early; they are frequently small, localized about the common bile duct and without widespread lymph-node involvement. The gallbladder (if present), as well as the proximal ductal system, is markedly distended. Eighteen of the 77 malignant bile duct tumors reported by 37

D

Fig 1·3.-Management of tumors of middle third of bile duct. A, Dilatation and intubation of obstructing tumor with T tube for nonresectable tumor. B, Ductenteric (choledochoduodenostomy or choledochojejunostomy) bypass anastomosis proximal to nonresectable tumor. C, Excision of tumor with duct-enteric (choledochoduodenostomy or choledochojejunostomy) anastomosis. For quite small, localized tumors, excision and end-to-end duct anastomosis may be possible. D, Hepatic resection and intrahepatic cholangiojejunostomy may be indicated for certain unusual lesions when free communication between left and right intrahepatic ductal systems remains.

Warren et al M were located in the intrapancreatic common duct. Fifteen patients were treated by pancreaticoduodenectomy; at the time of the report, 9 of them had survived for more than 1 year and 2 for more than 3 years. Of the 2 patients of Ingis and Farmer12 treated by pancreaticoduodenectomy, 1 lived for 3 years 38

9 months, the other for 9 months. Eleven of our 13 patients with distal-third lesions underwent operations. A duct enteric bypass and a cholecystojejunostomy were both utilized in one case (Fig 14, A and B); pancreaticoduodenectomies were performed on the other 9 patients (Fig 14, C). Jaundice was relieved and the period of palliation was considered good or excellent for all 11 patients. At the time of our report, 8 patients had died, 5 of them having survived for more than 1 year. Five patients were alive 1,1,2,10 and 15 years, respectively, after pancreaticoduodenectomy; these results support the increased effectiveness of en bloc resection for primary bile duct tumors, which, unfortunately, owing to involvement of the hepatic artery or portal vein or extension into the liver, has been utilized infrequently for middle- and upperthird tumors. Endoscopic evaluation of the ductal system at the time of operation may reduce the number of tumors considered for resection but will undoubtedly improve the survival rate of those patients whose tumors are resected. ,

Papillary Tumors. - Extensive intraductal papillary tumors were encountered in 3 of our patients. On the basis of microscopic examination, Stewart et aU classified 21 of 424 bile duct tumors as differentiated papillary carcinomas. Ross and his colleagues 12 encountered 2 papillary tumors in their 103 cases of carcinoma of the bile ducts: one patient died 13 months after the operation, the other after 30 months. These somewhat unusual, diffuse, malig. nant tumors are probably best treated by tube intubation. Their susceptibility to irradiation should be evaluated. A choledochojejunostomy was performed in one of our patients and T tubes were inserted in the common ducts of the other two. Palliation was considered good in one patient and fair in two. One patient lived for 2 112 years after T-tube intubation. Hepatic Transplantation. - Terblanche et al. 52 were of the opinion in 1972 that patients with bile duct tumors should not be considered for liver transplantation until the survival rate after palliative management had been improved. Starzl55 discussed three patients who had small bile duct carcinomas obstructing the confluence of the hepatic ducts and who were treated by orthotopic liver transplantation. One patient died after the transplantation; the other two were alive, one 15 months and one 9 months after the operation. Inasmuch as the tendency ofsome of these tumors to grow slowly is well recognized, additional time will be necessary for the evaluation of the role of hepatic transplantation as a possible additional palliative treatment for this disease. ADJUNCTIVE TREATMENT.-The role of irradiation therapy in the treatment of bile duct cancer has never been adequately eval39

Cholecystojejunostomy

Fig 14.-Methods of treating ductal (intrapancreatic) bile duct obstruction. A, Cholecystojejunostomy with jejunojejunostomy will decompress biliary system when nonresectable tumor is distal to junction of cystic and common hepatic ducts. Free communication between gallbladder and proximal biliary system is demonstrable by injection of radiopaque dye into gallbladder prior to anastomosis. B. Duct-enteric (choledochoduodenostomy or choledochojejunostomy) bypass anastomosis when gallbladder is absent or when nonresectable tumor obstructs communication of cystic and common bile ducts. C, Excision of local~ ized tumor in distal (intrapancreatic) portion of common duct by pancreaticoduodenal resection (Whipple's operation) with reconstruction by anastomosis\ of bile duct. pancreas and stomach to jejunum. as indicated.

40

uated. It is often stated that these tumors are radioresistant, although the basis for this statement is difficult to document. Possibly the acellular, fibrotic histologic structure of the tumor suggests that it would be unresponsive to treatment. Green and associates·'i6 described 4 patients with well-differentiated adenocarcinoma of the common hepatic duct who were treated with cobalt teletherapy. Two also had 5-fluorouracil treatments and two underwent T-tube choledochostomy. Jaundice was alleviated in all four patients. The duration of survival after operation was 7-17 months. The two patients who recei ved radiotherapy alone had survival times similar to those of the two treated with a palliative operation and radiotherapy. One of the patients treated with T-tube intubation and radiotherapy was found at autopsy'to' have extensive fibrosis of the common hepatic and common bile ducts, but there was no evidence on gross inspection or random histologic section of residual tumor. Terblanche et al.52 proposed radiotherapy after T- or U-tube tumor intubation, and our limited experience has encouraged us to give such combined therapy further evaluation. If radiotherapy is to be combined with surgical exploration, metal clips should be used to mark the site of the tumor to help direct the x-ray therapy. Cady57 described the fate of the infusion catheter and the hepatic artery in 81 consecutive primary operative hepatic arterial catheterizations with a standard Teflon catheter. These patients had a variety of primary and metastatic hepatic or biliary carcinomas' and resection of the primary colon cancer or dilatation or intubation of an obstructing bile duct carcinoma was sometimes performed during the operative procedure for the insertion of the arterial cannula. The specific effects of arterial infusion on the neoplasm were not evaluated. Suggestive improvement of hepatomas, of metastases from colon cancer and of islet cell'carcinoma of the pancreas resulting from infusion chemotherapy and the lack of response of these tumors to systemic chemotherapy are mentioned. However, the effect on bile duct carcinoma is not described. There was a median-proved patency time of the arterial catheter of 12 weeks. Complications directly related to catheter positioning and location were not serious. Eleven percent of patients manifest acid-peptic digestive disease; two thirds of them died of massive gastrointestinal hemorrhage. According to the studies of Parke et al.,5s the arterial blood supply of the extrahepatic biliary tract usually is derived from the hepatic artery and from the retroduodenal branch of the gastroduodenal artery. The effective selective delivery of arterially infused chemotherapy would require infusion via both of these vessels. It might be anticipated that under these circumstances the incidence of gastroduodenal mucosal inflammation would be increased. 41

After operating on 8 of their 14 patients with hepatic duct carcinoma, Ingis and Farmer12 administered 5-fiuorouracil therapy on a weekly basis, either orally or intravenously. Two patients received cobalt therapy with 2,500 to 5,000 rad administered locally to the area of carcinoma, followed by a course of 5-fluorouracil therapy. In one case, cobalt therapy with 2,400 rad was the sole treatment. Neither systemic chemotherapy nor radiation therapy (nor a combination thereof) had any effect on the survival rates of these patients. SUMMARY The current results of bile duct cancer therapy are unsatisfactory. Few patients are cured of the disease, and the majority are dead within 2 years after the operation. Nevertheless, in some cases the tumor is surprisingly slow-growing, and extended periods of palliation may be provided, even in nonresectable lesions. Correction of jaundice by resection, intubation or bypass procedures will give complete symptomatic relief to an astonishingly high percentage of these patients for months-to certain patients, for years. Several relatively recent developments mark the way for future progress in the management of this disease. Improving the accuracy in the diagnosis of this tumor, a procedure that is often quite difficult, may reveal that there is a higher incidence of this disease than previously thought; indeed, the tumor may not be as rare as it is currently considered. The new diagnostic aids of endoscopic retrograde choledochopancreatography and percutaneous transhepatic cholangiography are of assistance in diagnosing and localizing these tumors preoperatively, so that problems to be encountered at the time of operation may be considered and proposed operative procedures may be planned in advance. Intubation of the tumor and ducts by means of a U tube promises to provide a more lasting palliative conduit for bile through the tumor. The effectiveness of tube intubation followed by irradiation therapy needs further evaluation. Current chemotherapy treatment has not been promising, but new agents and combinations of various drugs may be found that will extend palliation. More radical en bloc resection of upper-third lesions should be carefully evaluated in selected cases. The results of current trials of hepatic transplantation will be of great interest.

42

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