Carcinoma of the Extrahepatic Bile Ducts A Ten Year Experience in Hawaii Allan A. Inouye, MD, Honolulu, Hawaii Thomas J. Whelan, Jr, MD, Honolulu, Hawaii
Extrahepatic bile duct and gallbladder carcinoma is seen most frequently in Israelis, American Indians, and Japanese [I]. Figures quoted on the incidence of these diseases are suspect due to the inaccuracy of preoperative diagnosis, the reluctance of surgeons to biopsy incurable lesions, and the difficulty in localizing the primary site, even at autopsy [2]. However, Waterhouse et al [I] have placed the annual, ageadjusted frequency per 100,000 males at 7.5,6.5, and 5.4 for the Israeli, Indian, and Japanese,populations, respectively. The Japanese in Hawaii retain the high risk of those from their country of origin, with an annual incidence of 3.8 per 100,000 men. In the hospitals of the University of Hawaii Surgical Program, interest in bile duct carcinoma has been stimulated by the large number of Japanese patients presenting and the frequency with which the disease is encountered. The present study constitutes a review of our clinical experience with malignant tumors of the extrahepatic biliary tree. Material and Methods The Kuakini Medical Center, Saint Francis Hospital, and the Queen’s Medical Center, hospitals in the University Surgical Program, provided the patient material for the present study. All patients whose charts recorded major diagnoses of “extrahepatic bile duct carcinoma” between 1966 and 1975 were reviewed. Patients with ampullary, pancreatic, cystic duct, or gallbladder carcinoma were excluded, as were those with cholangiocarcinoma. Patients who lacked biopsy or autopsy proof of carcinoma of the bile ducts were not included. Finally, those patients whose “definitive” laparotomies establishing the diagnosis of carcinoma were not within the time period of this series were also omitted. The study population, therefore, represented patients with tissue-proven extrahepatic bile duct carcinoma who were diagnosed between 1966 and 1975. From the Department of Surgery, University of Hawaii John A. Burns School of Medicine and Integrated Surgical Residency Program, Honolulu, Hawaii. Reprint requests should be addressed to Thomas J. Whelan, Jr, MD, University of Hawaii School of Medicine, 1356 Lusitana Street, Suite 606, Honolulu, Hawaii 96813. Presented at the Forty-Ninth Annual Meeting of the Pacific Coast Surgical Association, Newport Beach, California, February 19-22. 1978.
90
Patients were divided according to the anatomic classification of Longmire [3] into those with upper, middle, or lower third tumors. Lesions in the upper third of the extrahepatic biliary tree were located above the origin of the cystic duct. Middle third lesions occurred between the origin of the cystic duct and the superior border of the pancreas. Intrapancreatic lesions exclusive of the ampulla were classified as lower third. In all cases the classifications were made on the basis of the surgeon’s findings at laparotomy and/or the pathologist’s conclusions at autopsy. The majority of patients died a short time after diagnosis, and sufficiently detailed follow-up data could be obtained from hospital charts. Patients who did not die in university-affiliated hospitals were followed through the Tumor Registry or through correspondence with their private physicians. The charts of fifty-seven patients were finally selected for detailed review. There were twenty-five patients with upper third lesions, five with middle third lesions, and twenty-seven with lower third lesions. Clinical Data. Sex and age: Thirty-seven males and twenty females comprised the study group. Male PI%dominance, therefore, was almost 21. The peak incidence of bile duct carcinoma occurred in the seventh and eighth decades. (Figure 1.) However, nine patients were more than eighty years old. The average age for the entire population was sixty-seven years (range, 20 to 89 years). Race: The disease occurred predominantly in Japanese patients (58 per cent), and they outnumbered Caucasians, Chinese, and Filipinos by more than 6:l. (Figure 2.) Diagnosis
Symptoms. All but two patients presented to the hospital within six months of the onset of symptoms. More than half were hospitalized within one month. The most frequent complaints were abdominal pain, either diffuse or localized to the upper abdomen (49 per cent), “jaundice” (49 per cent), diarrhea and clay-colored stools (49 per cent), or dark tea-colored urine (42 per cent). Physical Examination. Fifteen patients (26 per cent) had no abnormal physical findings other than confirmation of scleral icterus or jaundice. The most common finding was hepatomegaly, occurring in 46 per cent of patients. An enlarged gallbladder could be palpated in fifteen patients (26 per cent), and ten of these fifteen were found to have middle or lower third lesions. Abdominal tenderness was elicited in thirteen patients (23 per cent).
The AmerlcsnJournalot Surgery
Extrahepatic
.‘,aboratc,r>, Tests. On complete blood count 61 per cent of patients were found to be anemic (hematocrit less than 46 per cent). Forty-four per cent had white blood cell counts in excess of 8,000. Ninety per cent had elevated bilirubin values. and 40 per cent of elevated initial bilirubin values were in excess of 15 mg/lOO ml. Alkaline phosphatase and serum glutamic oxalacetic transaminase (SGOT) levels were increased with almost equal frequency, 86 per cent and 79 per cent, respectively. Special Tests. The most frequently performed of the special diagnostic tests were the upper gastrointestinal series (36 patients) and the Rose Bengal liver scan (32 patients). The upper gastrointestinal series suggested the correct diagnosis in five cases, was negative in twenty-six, ard equivocal in five. The Rose Bengal scan indicated complete or high grade obstruction “consistent with extrahepatic carcinoma” in twenty-two of the thirty-two cases. Results were equivocal in eight, reflecting the interpreter’s inability to distinguish extra- from intrahepatic obstruction. More recently, ultrasonography, percutaneous transhepatic cholangiography. and endoscopic retrograde cholangiopancreatography have become available, but the number of cases in this series is small. Five of these test results were positive, one was equivocal, and one was negative.
20
Bile Duct Carcinoma
7
II-20
”
41-50 3-60 AGE
61-X
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80+
(YEARS:
Figure 1. Age distribution of fifty-seven patients with biie duct carcinoma shows peak incidence between sixty-one and eighty years of age.
40-
Treatment Of the fifty-seven patients in the series, fifty-two underwent laparotomy. Five patients had no operations, two with upper third and three with lower third carcinomas, ar.d their lesions were confirmed at autopsy. Upper Third and Middle Third Lesions. Twenty-eight of the thirty patients with upper and middle third lesions had operations. In nine patients with proximal lesions the surgeon could find no bile ducts for bypassing the obSt:-uction and closed the abdomen. One patient was lost to follow-up. The mean survival for the remaining eight patients was 5.7 months. Three patients died within thirty days of operation and could, therefore, be considered operative deaths. In the case of proximal lesions, however, death was almost uniformly due to the progression of the di.sease or its attendant septic complications. Two patients underwent cholecystostomy for palliation and died at seven days and nine months. Ten patients with upper third lesions had T tubes placed into their common or lower hepatic ducts. Three were lost to follow-up. The remaining seven survived thirteen days to fifteen months after operation (mean survival, 6 months). An additional two patients with middle third lesions underwent T-tube insertion with postoperative survivals of two and six months. Resection and choledochojejunostomy were performed in five patients, two with upper and three with middle third lesions. One patient with a middle third lesion achieved palliation for three years. The remaining patients survived an average of eight months after operation (range, 1 to 14 months). Lower Third Lesions. Twenty-four of the twenty-seven patients with lower third lesions underwent operation. One
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136, July 1978
JAP
CHN
CAUC
Fits
OTHER
Figure 2. Racial distrfbut~n indicates 58 per cent of patients in the series are of Japanese extraction.
patient had an open-and-close procedure and died three months postoperatively. Eight underwent some form of biliary-enteric bypass, and one underwent gastrojejunostomy only. All patients with palliative bypass died. One suffered an intraoperative cardiac arrest and died on the eleventh postoperative day. The others survived an average of ten months. All but one were dead within fourteen months, and the single exception lived three and a half years after choledochoduodenostomy. The immediate cause of death was a myocardial infarct, but autopsy revealed carcinoma of the distal duct with spread to the pancreas and regional nodes. Fourteen patients underwent pancreatoduodenectomy, and four (28 per cent) died as a direct result of operative complications. (Table I.) Three of these deaths were caused by jejunopancreatic leakage with resulting peritonitis. One died of uncontrollable bleeding, presumably secondary to
91
lnouye and Whelan
TABLE I
Causes of Death
the bile ducts was a direct or contributing factor in the patient’s death. Survival. Of the fifty-seven patients in this study, current follow-up is available on fifty-two (91 per cent). Two patients moved to the mainland United States and were lost to follow-up. Three were seen four months, one year, and two years prior to our writing this report, and no updated data are available. However, the patient seen one year ago was three years after resection of a middle third carcinoma and will be discussed herein with the survival group. Five patients had no operation and died four days to two months after hospitalization. Survival is computed from the date of hospital admission. The remaining forty-eight patients had some form of operative intervention, and survival is determined from the date of operation. (Figure 3.) More than half of the fifty-three patients died within four months of operation or hospitalization. Three fourths of the patients were dead within a year. Seven patients (13 per cent) lived more than two years, and three died subsequently, all with carcinoma. One patient with a middle third lesion was seen three years postoperatively and at that time had bone metastases. Three patients, all with lower third lesions and Whipple resections, have survived two, five, and six years after operation. None of these has evidence of metastases, and follow-up is current. None had any nodal involvement in the resected specimens. One had a poorly differentiated, one a well differentiated, and one a moderately well differentiated lesion. The patient who is now six years after operation had a prolonged course of 5-fluorouracil chemotherapy; the others had neither irradiation nor chemotherapy.
No. of Patients “Carcinomatosis” Cholangitis/sepsis Bleeding Gastrointestinal “Diathesis” Pulmonary Pancreas Anastomotic leak “Hemorrhagic pancreatitis” Hepatic failure Liver abscess Cardiac Cardiovascular accident No cause listed
16 15 7 5 2 6 4 3 1 4 3 3 1 7
Note: The total number of causes of death is greater than the number of patients who died because some patients had multiple causes.
diffuse intravascular coagulation. Six of the ten survivors had ten complications. A leaking jejunopancreatic anastomosis caused a persisting pancreatic fistula in a patient who also had pneumonia and wound bleeding. Cholangitis occurred in two patients, one of whom developed liver failure and the other gastrointestinal bleeding. Subhepatic abscess, malabsorption, and atelectasis with penumonia occurred in one patient each. Three of the patients who underwent the Whipple procedure are still alive. Mean survival time of the seven patients who died was twenty months (range, 10 months to 4 years). Sepsis or cholsngitis were listed as primary causes of death in four patients, and two of these had developed recurrent cancer. An additional patient died of carcinomatosis. In two cases no cause of death was listed. Results
Mortality. Forty-nine patients are definitely known to be dead. The causes of death, listed in Table II, are based on autopsy data or registered causes of death if no autopsies were performed. In seven cases the date of death was the only information available. The patients listed as dying from cardiac causes all had residual carcinoma at death, as did the patient who suffered a cerebrovascular accident. Therefore, in all known cases carcinoma of
TABLE II
Patient FS z KY LM
92
Pathology
Since the generally better survivals in patients who underwent pancreatoduodenectomy may have been due to more favorable lesions, pathology reports and operative summaries were reviewed to determine the extent of tumor spread. All of the bile duct tumors in this study were adenocarcinomas. Three of the patients who underwent Whipple resections had
Operative Deaths Age (YrV Sex 00/M 62/M 77/F 71/M 71/F
Race
Operation
Postop Death (days)
Jw Jpn Jpn Jpn
Cholecystojejunostomy Whipple Whipple Whipple Whipple
11 9 19 23 14
Cauc
Cause of Death Cardiac arrest, sepsis Uncontrolled bleeding ,Hemorrhagic pancreatitis, jejunopancreatic leak with abscess Jejunopancreatic leak with peritonitis Jejunopancreatic leak with peritonitis
The American Journal of Surgery
Extrahepatic
nodal involvement and one had omental implants. The remaining ten patients had carcinoma confined to the bile duct and adjacent pancreas. The patients having bypass operations were believed to have “unresectable” lesions in three cases, but the exact extent of involvement was not specified in the operative note. Nodes were involved in three and peritoneal implants were present in two. Only one patient had “local” involvement, without nodal, liver, or other distant metastases. The group of patients who underwent pancreatoduodenectomy, therefore, were undoubtedly selected on the basis of more favorable and localized lesions. Gallstones. Charts were also reviewed for histories of previous biliary tract disease. Six patients had previous cholecystectomies with or without common duct explorations two months to six years prior to “definitive” laparotomy. In four cases these operations occurred within eighteen months of the exploration for cancer. In addition, fourteen gallbladders were removed at laparotomies performed for cancer, and six of these contained stones. One patient was found to have stones in his gallbladder at autopsy. Therefore, a total of eleven patients had recent or concomitant stones, 19 per cent of the total number of’patients. Comments
The striking finding in this study is the preponderance of elderly Japanese with extrahepatic bile duct cancer. Japanese people comprise 27 per cent of’ the population of Hawaii and 26 per cent of the population of Oahu. Twenty-eight per cent of Hawaii’s and 29 per cent of Oahu’s populations are Caucasian [4]. The number of Caucasian and Japanese people in Hawaii and Oahu, therefore, are approximately equal, but Japanese with bile duct cancer outnumber Caucasians by more than 6:l. The reasons for Japanese predominance are not currently known. Chemical agents such as o-aminoazotoluene, methylcholanthrene, and Aramite have been shown to induce biliary tract cancer in animals following d:.rect contact or ingestion [5-71. The recently documented association between ulcerative colitis and bi.le duct cancer indicates that stasis and infection m.ay also play a role [8,9]. A high incidence of bile duct cancer in the Orient where biliary parasites (Ascaris lumbricoides and Clonorchis sinensis) and intrahepatic stones and strictures are prevalent further suggests a possible relationship. It is tempting, therefore, to postulate that inflammation or carcinogens within the bile duct could predispose to tumor growth, but definitive proof is still lacking.
Volume 136, July 1978
Bile Duct Carcinoma
,
.
Total populotlon 53 dead IX
?
*
Upper C,
ies~ons21
i I \
0
LOWLY V3
27 00tld5
“ot
risk”
ot least
2 yeor~ 3ot1ents
1
MONTHS Figure 3. The poor prognosis in extrahepatic bile duct carcinoma is shown. On/y patients with lower third lesion had prolonged survival, and there were on/y three such patients.
The generally poor survival which has been previously observed in carcinoma of the proximal extrahepatic biliary system [2,10] is again seen in this study. Resection of the left lobe of the liver with hepaticojejunostomy was not attempted in any of the patients in the present series. Its reported success has been limited, and only two of the eight patients reported by Longmire [3] lived more than two years after operation. In 1972, Terblanche, Saunders, and Louw [II] reported prolonged palliation in proximal tumors with a U-tube bypass procedure. The major advantage of the U tube is that it allows ready replacement if occlusion or displacement occurs. Indeed, in two of our patients the T tubes became occluded, necessitating reoperation in one. We have placed three U tubes over the past year for proximal bile duct cancer (these patients were not included in the study series), and palliation has been good within a limited follow-up period. Given the poor results achieved with bypass procedures, the U tube appears to offer a reasonable alternative for prolonged palliation. Of the three locations of bile duct cancer, the lower third offers the best chance for cure. Pancreatoduodenectomy is the procedure of choice for circumscribed tumors. Some authors have questioned the value of the Whipple operation, particularly in treating carcinoma of the head of the pancreas [12,13]. However, reported five year survivals after resection for bile duct cancer are consistently better than for pancreatic neoplasms, with figures averaging approximately 23 per cent [14-161. Survival after Whipple resection for pancreatic carcinoma averaged
93
lnouye and Whelan
only 10.5 per cent in the same series. Certainly, patients with distant metastases, invasion of the portal vein or superior mesenteric vessels, or positive nodes in the lesser omentum and celiac axis should have palliative biliary bypass. Other patients with bile duct carcinoma warrant a Whipple operation in an attempt at cure. Six of the seven patients who lived more than two years underwent pancreatoduodenectomy, and two of these are five year survivors. However, the mortality with the procedure was high (28 per cent) and the morbidity significant, with six of ten survivors suffering complications. Much of the serious morbidity arose from the jejunopancreatic anastomosis, and leakage at this point was a contributing factor in the deaths of three patients. It has been argued that total pancreatectomy obviates the dangers of the jejunopancreatic anastomosis without creating prohibitive long-term complications [17,18]. Goldsmith, Ghosh, and Huvos [19] and Brunschwig [20] have advocated ligation of the pancreatic duct and suturing of the cut end of the pancreas as an alternative to jejunal implantation. Autopsy of patients with either ligation of the pancreatic duct or implantation of the pancreas into the jejunum showed similar changes in the pancreas, with preservation of islet cell morphology [19]. These maneuvers warrant consideration in avoidance of complications at the jejunopancreatic anastomosis.
poor, and all patients followed died within seventeen months of hospitalization or operation. In patients undergoing bypass procedures for lower third (intrapancreatic) lesions, palliation averages ten months. The Whipple operation, performed in fourteen selected patients with favorable lesions, affords palliation averaging twenty months, and five patients were long-term survivors, including two with five year cures. However, morbidity and mortality for the Whipple procedure is high. Methods for improving palliation in upper third lesions and lowering morbidity and mortality from pancreatoduodenectomy are proposed. References 1.
2.
3. 4. 5. 6.
7.
8.
Conclusions 9.
(1) Extrahepatic bile duct carcinoma in Hawaii is found predominantly in the Japanese population (2) Survival and palliation for upper third lesions are limited. Newer technics may provide longer palliation. (3) Pancreatoduodenectomy offers the only chance for cure in lower third lesions and is the preferred method of treatment. Prolonged palliation may be achieved in patients who are not cured by Whipple resection. (4) Pancreatoduodenectomy was associated in this series with high mortality and morbidity which are due predominantly to leakage at the jejunopancreatic anastomosis. Summary
A ten year review (1966-1975) of extrahepatic bile duct carcinoma in three major Honolulu hospitals is nresented. Fiftv-seven natients satisfied the criteria for the study. The disease occurs predominantly in the Japanese population. Survival of patients with upper third lesions proximal to the cystic duct is
94
10. 11.
12.
13.
14. 15. 16.
17.
18. 19.
20.
WaterhouseJ, Muir
C, Carrea P, et al (eds): Cancer Incidence in Five Continents. International Agency for Research on Cancer Scientific Publications, vol 3, 1976. Hart J, Shani M, Modan 8: Epidemiological aspects of gallbladder and biliary tract neoplasm. Am J Public Health 62: 36, 1972. Longmire WP: Tumors of the extrahepatic biliary radicals. Curr Probl Cancer l(2): 1, 1976. Hawaii State Government, Department of Health Statistics, 1976. Former JG, Leffall LD: In [ 71. Nelson AA, Woodard G: Tumors of urinary bladder, gall bladder, and liver in dogs fed o-aminoazotoluene or p-dimethylaminoazobenzene. J Nat/ Cancer lnst 13: 1497, 1952-1953. Sternberg SS, Popper H, Oser BL. et al: Gallbaldder and bile duct adenocarcinoma in dogs after long term feeding of Aramite. Cancer 13: 780, 1960. Akwari OE, Van Heerden JA, Foulk WT, et al: Cancer of the bile ducts associated with ulcerative colitis. Ann Surg 181: 303, 1975. Morowitz DA, Glagov S, Dardal E, et al: Carcinoma of the biliary tract complicating chronic ulcerative colitis. Cancer 27: 356, 1971. Ross AP, Braasch JW, Warren KWz Carcinoma of the proximal bile ducts. Surg Gynecol Obstet 136: 923, 1973. Terblanche J, Saunders SJ, Louw JH: Prolonged palliation in carcinoma of the main hepatic duct junction. Surgery 71: 720, 1972. Crile G: The advantage of bypass operations over radical pancreatoduodenectomy in the treatment of pancreatic carcinoma. Surg Gynecol Obsfet 130: 1048, 1970. Shapiro TM: Adenocarcinoma of the pancreas: a statistical analysis of biliary bypass vs Whipple resection in good risk patients. Ann Surg 182: 715, 1975. Aston SJ, Longmire WP: Pancreaticoducdenal resection: twenty years’ experience. Arch Surg 106: 8 13, 1973. Warren KW, Choe DS, Plaza J, et al: Results of radical resection for periampullary cancer. Ann Surg 181: 534, 1975. Sato T. Saitoh Y. Noto N, et al: Follow-up studies of radical resection for pancreaticoduodenal cancer. Ann Surg 186: 581, 1977. Collins JJ. Craighead JE. Brooks JR: Rationale for total pancreatectomy for carcinoma of the pancreatic head. IV Engl J Med 274: 599, 1966. ReMine WH, Priestley, JT, Judd ES, et al: Total pancreatectomy. Ann Sura 172: 595. 1970. Gotdsmkh ES, Ghosh BC, Huvos AG: Ligation versus implantation of the pancreatic duct after pancbaticoduodenectcmy. Surg Gynecal Obstet 132: 87, 1971. Brunschwig A: A report upon a technique for pancreaticoduodenectomy. Surg Gynecal Obsfet 118: 263, 1964.
The American Journal of Surgery
Extrahepatic
Discussion Ronald K. Tompkins (Los Angeles, CA): Drs. Inouye an,l Whelan have presented a very impressive series of well ev:duat,ed patients with carcinomas of the extrahepatic ducts. Their series differs somewhat from other American reljorts in that almost half their patients were more than seventy years old and many more than half were Oriental. Of interest also was that 47 per cent of their patients had lesions of the distal third of the bile duct, a location where thl chance of surgical cure is greatest. In a series recently reported from our institution (Ann Surg 178: 333, 1973) the frequency of distal third lesions was only 20 per cent of sixty-three cases. Whether these age and racial differences have influenced the anatomic distribution of the lesions or give a clue to their possible causes remains speculative. The survival figures quoted by the authors are about equal to those reported by others. (Slide) Of thirty-four patients we have treated with upper third lesions, five are currently alive. The longest survivor in this group is four ar d a half years after a palliative bypass, demonstrating the slow growth characteristics of some of these tumors. The authors have correctly pointed out that radical pancreatoduodenectomy offers the best chance for cure of those distal third lesions which have not metastasized. T:rey have also reaffirmed the seriousness of pancreatic leaks after Whipple procedures. Although our group has had difficulties with leakage from pancreatojejunostomies, there have also been serious leaks from the oversewn cut end of the pancreas, so we cannot recommend this as an improvement in the technic of the Whipple procedure. We now favor anastomosis of the mucosa of the jejunum to the mucosa of the pancreatic duct when the latter is dilated. When the pancreatic duct is of normal caliber, we invag-, inate the cut end of the pancreas into the jejunum as securely as possible after placing a plastic tube into the pancreatic duct to stent it while healing takes place. (Slide) Of the thirteen patients we have treated with distal third lesions, ten have had Whipple procedures with no operative mortality and a 30 per cent five year survival. Five of t,he thirteen are still alive, two living ten and fifteen years since resection. Finally, the authors have clearly pointed out the great difficulties often encountered in making a definitive diagnosis at operation in these patients. For the past five years we have relied more and more upon operative choledochoscopy to enable us to biopsy the obstruction under direct vision. In addition, we have observed some patients who have had more than one site of tumor within the biliary system, and these patients have been spared a needless radical procedure. We continue to be enthusiastic in the use cjf this new diagnostic tool.
Orville F. Grimes (San Francisco, CA): Three years ago we presented our experience at the University of California, San Francisco before this association with extrahepatic bile duct carcinoma exclusive of the papillary lesions. In general
Volume 136,July 1978
Bile Duct Carcinoma
our resu1t.s were almost identical with those presented herein. These a.re peculiar and frustrating malignancies. They tend toward local spread, enhanced by the actual structural anatomy of the bile ducts. Actually, the ducts are merely thin-walled tubes of fibrous tissue with a few wisps of isolated and scattered muscle fibers. They are also lined with a thin layer of epithelium which extends through the entire wall to form glands on the outer surface of the ducts, thereby allowing malignant cells originating in the mucosa to reach the surface and the periductal regions by direct growth along this glandular system. Furthermore, the outer layers are richly supplied with nerves and lymphatics, and invasion of periductal tissues is common even when the lesion is quite small. (Slide) This specimen appears to be a rather favorable lesion demonstrated by endoscopic retrograde cholangiopancreatography (ERCP), well restricted to the lower portion of the common bile duct. (Slide) Upon laboratory study, perineural invasion directly adjacent to this rather large nerve can be seen. (Slide) A little farther away, there is another nerve which appears to be almost devoured by the metastatic malignancy. Perineural invasion is common and may extend for a considerable distance beyond the limits of the existing lesion. Even without lymph node metastases, and with presumably tumor-free margins of resection, perineural involvement is often the cause of failure. Thomas J. Whelan (closing): We are seeing extrahepatic bile duct cancer most frequently in elderly Japanese patients. This incidence occurs currently in those who were born in Japan and also first generation Japanese. It is going to be very interesting to see whether the prevalence of this disease persists in Japanese people who have lived in Hawaii a longer period of time. In a recent report from Korea (Kim YO, Kim YC, Kim IC, et al: ,l’ersonal communication), there were ninety-six cases of bsiliary carcinoma, sixty-six of which occurred in the extrahepatic bile ducts in one hospital over a ten year period. The Koreans are one of our most, recently migrating groups, and therefore, we may see an upswing on the right side of Dr. Inouye’s bar graph concerning ethnic group incidence. At the Central Regional Hospital in Okinawa, where the University of Hawaii participates in residency training of the house staff, many cases of extrahepatic bile duct carcinoma, demonstrated by use of the percutaneous transhepatic cholangiography, are also noted. Diagno;sis may be difficult. Recently an elderly Japanese patient was referred with the diagnosis of sclerosing cholangitis. This is a diagnosis that enters into the differential diagnosis., but it has been our experience that most of such cases have turned out eventually to be carcinoma of the extrahepatic bile duct system, sclerosing in type. These lesions may spread via perineural lymphatics, or spread directly along the ducts, or the lesions may he multicentric, all of which militate toward a nil prognosis in proximal third lesions.
95
Extrahepatic bile duct and gallbladder carcinoma is seen most frequently in Israelis, American Indians, and Japanese [I]. Figures quoted on the incidence of these diseases are suspect due to the inaccuracy of preoperative diagnosis, the reluctance of surgeons to biopsy incurable lesions, and the difficulty in localizing the primary site, even at autopsy [2]. However, Waterhouse et al [I] have placed the annual, ageadjusted frequency per 100,000 males at 7.5,6.5, and 5.4 for the Israeli, Indian, and Japanese,populations, respectively. The Japanese in Hawaii retain the high risk of those from their country of origin, with an annual incidence of 3.8 per 100,000 men. In the hospitals of the University of Hawaii Surgical Program, interest in bile duct carcinoma has been stimulated by the large number of Japanese patients presenting and the frequency with which the disease is encountered. The present study constitutes a review of our clinical experience with malignant tumors of the extrahepatic biliary tree. Material and Methods The Kuakini Medical Center, Saint Francis Hospital, and the Queen’s Medical Center, hospitals in the University Surgical Program, provided the patient material for the present study. All patients whose charts recorded major diagnoses of “extrahepatic bile duct carcinoma” between 1966 and 1975 were reviewed. Patients with ampullary, pancreatic, cystic duct, or gallbladder carcinoma were excluded, as were those with cholangiocarcinoma. Patients who lacked biopsy or autopsy proof of carcinoma of the bile ducts were not included. Finally, those patients whose “definitive” laparotomies establishing the diagnosis of carcinoma were not within the time period of this series were also omitted. The study population, therefore, represented patients with tissue-proven extrahepatic bile duct carcinoma who were diagnosed between 1966 and 1975. From the Department of Surgery, University of Hawaii John A. Burns School of Medicine and Integrated Surgical Residency Program, Honolulu, Hawaii. Reprint requests should be addressed to Thomas J. Whelan, Jr, MD, University of Hawaii School of Medicine, 1356 Lusitana Street, Suite 606, Honolulu, Hawaii 96813. Presented at the Forty-Ninth Annual Meeting of the Pacific Coast Surgical Association, Newport Beach, California, February 19-22. 1978.
90
Patients were divided according to the anatomic classification of Longmire [3] into those with upper, middle, or lower third tumors. Lesions in the upper third of the extrahepatic biliary tree were located above the origin of the cystic duct. Middle third lesions occurred between the origin of the cystic duct and the superior border of the pancreas. Intrapancreatic lesions exclusive of the ampulla were classified as lower third. In all cases the classifications were made on the basis of the surgeon’s findings at laparotomy and/or the pathologist’s conclusions at autopsy. The majority of patients died a short time after diagnosis, and sufficiently detailed follow-up data could be obtained from hospital charts. Patients who did not die in university-affiliated hospitals were followed through the Tumor Registry or through correspondence with their private physicians. The charts of fifty-seven patients were finally selected for detailed review. There were twenty-five patients with upper third lesions, five with middle third lesions, and twenty-seven with lower third lesions. Clinical Data. Sex and age: Thirty-seven males and twenty females comprised the study group. Male PI%dominance, therefore, was almost 21. The peak incidence of bile duct carcinoma occurred in the seventh and eighth decades. (Figure 1.) However, nine patients were more than eighty years old. The average age for the entire population was sixty-seven years (range, 20 to 89 years). Race: The disease occurred predominantly in Japanese patients (58 per cent), and they outnumbered Caucasians, Chinese, and Filipinos by more than 6:l. (Figure 2.) Diagnosis
Symptoms. All but two patients presented to the hospital within six months of the onset of symptoms. More than half were hospitalized within one month. The most frequent complaints were abdominal pain, either diffuse or localized to the upper abdomen (49 per cent), “jaundice” (49 per cent), diarrhea and clay-colored stools (49 per cent), or dark tea-colored urine (42 per cent). Physical Examination. Fifteen patients (26 per cent) had no abnormal physical findings other than confirmation of scleral icterus or jaundice. The most common finding was hepatomegaly, occurring in 46 per cent of patients. An enlarged gallbladder could be palpated in fifteen patients (26 per cent), and ten of these fifteen were found to have middle or lower third lesions. Abdominal tenderness was elicited in thirteen patients (23 per cent).
The AmerlcsnJournalot Surgery
Extrahepatic
.‘,aboratc,r>, Tests. On complete blood count 61 per cent of patients were found to be anemic (hematocrit less than 46 per cent). Forty-four per cent had white blood cell counts in excess of 8,000. Ninety per cent had elevated bilirubin values. and 40 per cent of elevated initial bilirubin values were in excess of 15 mg/lOO ml. Alkaline phosphatase and serum glutamic oxalacetic transaminase (SGOT) levels were increased with almost equal frequency, 86 per cent and 79 per cent, respectively. Special Tests. The most frequently performed of the special diagnostic tests were the upper gastrointestinal series (36 patients) and the Rose Bengal liver scan (32 patients). The upper gastrointestinal series suggested the correct diagnosis in five cases, was negative in twenty-six, ard equivocal in five. The Rose Bengal scan indicated complete or high grade obstruction “consistent with extrahepatic carcinoma” in twenty-two of the thirty-two cases. Results were equivocal in eight, reflecting the interpreter’s inability to distinguish extra- from intrahepatic obstruction. More recently, ultrasonography, percutaneous transhepatic cholangiography. and endoscopic retrograde cholangiopancreatography have become available, but the number of cases in this series is small. Five of these test results were positive, one was equivocal, and one was negative.
20
Bile Duct Carcinoma
7
II-20
”
41-50 3-60 AGE
61-X
71-80
80+
(YEARS:
Figure 1. Age distribution of fifty-seven patients with biie duct carcinoma shows peak incidence between sixty-one and eighty years of age.
40-
Treatment Of the fifty-seven patients in the series, fifty-two underwent laparotomy. Five patients had no operations, two with upper third and three with lower third carcinomas, ar.d their lesions were confirmed at autopsy. Upper Third and Middle Third Lesions. Twenty-eight of the thirty patients with upper and middle third lesions had operations. In nine patients with proximal lesions the surgeon could find no bile ducts for bypassing the obSt:-uction and closed the abdomen. One patient was lost to follow-up. The mean survival for the remaining eight patients was 5.7 months. Three patients died within thirty days of operation and could, therefore, be considered operative deaths. In the case of proximal lesions, however, death was almost uniformly due to the progression of the di.sease or its attendant septic complications. Two patients underwent cholecystostomy for palliation and died at seven days and nine months. Ten patients with upper third lesions had T tubes placed into their common or lower hepatic ducts. Three were lost to follow-up. The remaining seven survived thirteen days to fifteen months after operation (mean survival, 6 months). An additional two patients with middle third lesions underwent T-tube insertion with postoperative survivals of two and six months. Resection and choledochojejunostomy were performed in five patients, two with upper and three with middle third lesions. One patient with a middle third lesion achieved palliation for three years. The remaining patients survived an average of eight months after operation (range, 1 to 14 months). Lower Third Lesions. Twenty-four of the twenty-seven patients with lower third lesions underwent operation. One
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136, July 1978
JAP
CHN
CAUC
Fits
OTHER
Figure 2. Racial distrfbut~n indicates 58 per cent of patients in the series are of Japanese extraction.
patient had an open-and-close procedure and died three months postoperatively. Eight underwent some form of biliary-enteric bypass, and one underwent gastrojejunostomy only. All patients with palliative bypass died. One suffered an intraoperative cardiac arrest and died on the eleventh postoperative day. The others survived an average of ten months. All but one were dead within fourteen months, and the single exception lived three and a half years after choledochoduodenostomy. The immediate cause of death was a myocardial infarct, but autopsy revealed carcinoma of the distal duct with spread to the pancreas and regional nodes. Fourteen patients underwent pancreatoduodenectomy, and four (28 per cent) died as a direct result of operative complications. (Table I.) Three of these deaths were caused by jejunopancreatic leakage with resulting peritonitis. One died of uncontrollable bleeding, presumably secondary to
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lnouye and Whelan
TABLE I
Causes of Death
the bile ducts was a direct or contributing factor in the patient’s death. Survival. Of the fifty-seven patients in this study, current follow-up is available on fifty-two (91 per cent). Two patients moved to the mainland United States and were lost to follow-up. Three were seen four months, one year, and two years prior to our writing this report, and no updated data are available. However, the patient seen one year ago was three years after resection of a middle third carcinoma and will be discussed herein with the survival group. Five patients had no operation and died four days to two months after hospitalization. Survival is computed from the date of hospital admission. The remaining forty-eight patients had some form of operative intervention, and survival is determined from the date of operation. (Figure 3.) More than half of the fifty-three patients died within four months of operation or hospitalization. Three fourths of the patients were dead within a year. Seven patients (13 per cent) lived more than two years, and three died subsequently, all with carcinoma. One patient with a middle third lesion was seen three years postoperatively and at that time had bone metastases. Three patients, all with lower third lesions and Whipple resections, have survived two, five, and six years after operation. None of these has evidence of metastases, and follow-up is current. None had any nodal involvement in the resected specimens. One had a poorly differentiated, one a well differentiated, and one a moderately well differentiated lesion. The patient who is now six years after operation had a prolonged course of 5-fluorouracil chemotherapy; the others had neither irradiation nor chemotherapy.
No. of Patients “Carcinomatosis” Cholangitis/sepsis Bleeding Gastrointestinal “Diathesis” Pulmonary Pancreas Anastomotic leak “Hemorrhagic pancreatitis” Hepatic failure Liver abscess Cardiac Cardiovascular accident No cause listed
16 15 7 5 2 6 4 3 1 4 3 3 1 7
Note: The total number of causes of death is greater than the number of patients who died because some patients had multiple causes.
diffuse intravascular coagulation. Six of the ten survivors had ten complications. A leaking jejunopancreatic anastomosis caused a persisting pancreatic fistula in a patient who also had pneumonia and wound bleeding. Cholangitis occurred in two patients, one of whom developed liver failure and the other gastrointestinal bleeding. Subhepatic abscess, malabsorption, and atelectasis with penumonia occurred in one patient each. Three of the patients who underwent the Whipple procedure are still alive. Mean survival time of the seven patients who died was twenty months (range, 10 months to 4 years). Sepsis or cholsngitis were listed as primary causes of death in four patients, and two of these had developed recurrent cancer. An additional patient died of carcinomatosis. In two cases no cause of death was listed. Results
Mortality. Forty-nine patients are definitely known to be dead. The causes of death, listed in Table II, are based on autopsy data or registered causes of death if no autopsies were performed. In seven cases the date of death was the only information available. The patients listed as dying from cardiac causes all had residual carcinoma at death, as did the patient who suffered a cerebrovascular accident. Therefore, in all known cases carcinoma of
TABLE II
Patient FS z KY LM
92
Pathology
Since the generally better survivals in patients who underwent pancreatoduodenectomy may have been due to more favorable lesions, pathology reports and operative summaries were reviewed to determine the extent of tumor spread. All of the bile duct tumors in this study were adenocarcinomas. Three of the patients who underwent Whipple resections had
Operative Deaths Age (YrV Sex 00/M 62/M 77/F 71/M 71/F
Race
Operation
Postop Death (days)
Jw Jpn Jpn Jpn
Cholecystojejunostomy Whipple Whipple Whipple Whipple
11 9 19 23 14
Cauc
Cause of Death Cardiac arrest, sepsis Uncontrolled bleeding ,Hemorrhagic pancreatitis, jejunopancreatic leak with abscess Jejunopancreatic leak with peritonitis Jejunopancreatic leak with peritonitis
The American Journal of Surgery
Extrahepatic
nodal involvement and one had omental implants. The remaining ten patients had carcinoma confined to the bile duct and adjacent pancreas. The patients having bypass operations were believed to have “unresectable” lesions in three cases, but the exact extent of involvement was not specified in the operative note. Nodes were involved in three and peritoneal implants were present in two. Only one patient had “local” involvement, without nodal, liver, or other distant metastases. The group of patients who underwent pancreatoduodenectomy, therefore, were undoubtedly selected on the basis of more favorable and localized lesions. Gallstones. Charts were also reviewed for histories of previous biliary tract disease. Six patients had previous cholecystectomies with or without common duct explorations two months to six years prior to “definitive” laparotomy. In four cases these operations occurred within eighteen months of the exploration for cancer. In addition, fourteen gallbladders were removed at laparotomies performed for cancer, and six of these contained stones. One patient was found to have stones in his gallbladder at autopsy. Therefore, a total of eleven patients had recent or concomitant stones, 19 per cent of the total number of’patients. Comments
The striking finding in this study is the preponderance of elderly Japanese with extrahepatic bile duct cancer. Japanese people comprise 27 per cent of’ the population of Hawaii and 26 per cent of the population of Oahu. Twenty-eight per cent of Hawaii’s and 29 per cent of Oahu’s populations are Caucasian [4]. The number of Caucasian and Japanese people in Hawaii and Oahu, therefore, are approximately equal, but Japanese with bile duct cancer outnumber Caucasians by more than 6:l. The reasons for Japanese predominance are not currently known. Chemical agents such as o-aminoazotoluene, methylcholanthrene, and Aramite have been shown to induce biliary tract cancer in animals following d:.rect contact or ingestion [5-71. The recently documented association between ulcerative colitis and bi.le duct cancer indicates that stasis and infection m.ay also play a role [8,9]. A high incidence of bile duct cancer in the Orient where biliary parasites (Ascaris lumbricoides and Clonorchis sinensis) and intrahepatic stones and strictures are prevalent further suggests a possible relationship. It is tempting, therefore, to postulate that inflammation or carcinogens within the bile duct could predispose to tumor growth, but definitive proof is still lacking.
Volume 136, July 1978
Bile Duct Carcinoma
,
.
Total populotlon 53 dead IX
?
*
Upper C,
ies~ons21
i I \
0
LOWLY V3
27 00tld5
“ot
risk”
ot least
2 yeor~ 3ot1ents
1
MONTHS Figure 3. The poor prognosis in extrahepatic bile duct carcinoma is shown. On/y patients with lower third lesion had prolonged survival, and there were on/y three such patients.
The generally poor survival which has been previously observed in carcinoma of the proximal extrahepatic biliary system [2,10] is again seen in this study. Resection of the left lobe of the liver with hepaticojejunostomy was not attempted in any of the patients in the present series. Its reported success has been limited, and only two of the eight patients reported by Longmire [3] lived more than two years after operation. In 1972, Terblanche, Saunders, and Louw [II] reported prolonged palliation in proximal tumors with a U-tube bypass procedure. The major advantage of the U tube is that it allows ready replacement if occlusion or displacement occurs. Indeed, in two of our patients the T tubes became occluded, necessitating reoperation in one. We have placed three U tubes over the past year for proximal bile duct cancer (these patients were not included in the study series), and palliation has been good within a limited follow-up period. Given the poor results achieved with bypass procedures, the U tube appears to offer a reasonable alternative for prolonged palliation. Of the three locations of bile duct cancer, the lower third offers the best chance for cure. Pancreatoduodenectomy is the procedure of choice for circumscribed tumors. Some authors have questioned the value of the Whipple operation, particularly in treating carcinoma of the head of the pancreas [12,13]. However, reported five year survivals after resection for bile duct cancer are consistently better than for pancreatic neoplasms, with figures averaging approximately 23 per cent [14-161. Survival after Whipple resection for pancreatic carcinoma averaged
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lnouye and Whelan
only 10.5 per cent in the same series. Certainly, patients with distant metastases, invasion of the portal vein or superior mesenteric vessels, or positive nodes in the lesser omentum and celiac axis should have palliative biliary bypass. Other patients with bile duct carcinoma warrant a Whipple operation in an attempt at cure. Six of the seven patients who lived more than two years underwent pancreatoduodenectomy, and two of these are five year survivors. However, the mortality with the procedure was high (28 per cent) and the morbidity significant, with six of ten survivors suffering complications. Much of the serious morbidity arose from the jejunopancreatic anastomosis, and leakage at this point was a contributing factor in the deaths of three patients. It has been argued that total pancreatectomy obviates the dangers of the jejunopancreatic anastomosis without creating prohibitive long-term complications [17,18]. Goldsmith, Ghosh, and Huvos [19] and Brunschwig [20] have advocated ligation of the pancreatic duct and suturing of the cut end of the pancreas as an alternative to jejunal implantation. Autopsy of patients with either ligation of the pancreatic duct or implantation of the pancreas into the jejunum showed similar changes in the pancreas, with preservation of islet cell morphology [19]. These maneuvers warrant consideration in avoidance of complications at the jejunopancreatic anastomosis.
poor, and all patients followed died within seventeen months of hospitalization or operation. In patients undergoing bypass procedures for lower third (intrapancreatic) lesions, palliation averages ten months. The Whipple operation, performed in fourteen selected patients with favorable lesions, affords palliation averaging twenty months, and five patients were long-term survivors, including two with five year cures. However, morbidity and mortality for the Whipple procedure is high. Methods for improving palliation in upper third lesions and lowering morbidity and mortality from pancreatoduodenectomy are proposed. References 1.
2.
3. 4. 5. 6.
7.
8.
Conclusions 9.
(1) Extrahepatic bile duct carcinoma in Hawaii is found predominantly in the Japanese population (2) Survival and palliation for upper third lesions are limited. Newer technics may provide longer palliation. (3) Pancreatoduodenectomy offers the only chance for cure in lower third lesions and is the preferred method of treatment. Prolonged palliation may be achieved in patients who are not cured by Whipple resection. (4) Pancreatoduodenectomy was associated in this series with high mortality and morbidity which are due predominantly to leakage at the jejunopancreatic anastomosis. Summary
A ten year review (1966-1975) of extrahepatic bile duct carcinoma in three major Honolulu hospitals is nresented. Fiftv-seven natients satisfied the criteria for the study. The disease occurs predominantly in the Japanese population. Survival of patients with upper third lesions proximal to the cystic duct is
94
10. 11.
12.
13.
14. 15. 16.
17.
18. 19.
20.
WaterhouseJ, Muir
C, Carrea P, et al (eds): Cancer Incidence in Five Continents. International Agency for Research on Cancer Scientific Publications, vol 3, 1976. Hart J, Shani M, Modan 8: Epidemiological aspects of gallbladder and biliary tract neoplasm. Am J Public Health 62: 36, 1972. Longmire WP: Tumors of the extrahepatic biliary radicals. Curr Probl Cancer l(2): 1, 1976. Hawaii State Government, Department of Health Statistics, 1976. Former JG, Leffall LD: In [ 71. Nelson AA, Woodard G: Tumors of urinary bladder, gall bladder, and liver in dogs fed o-aminoazotoluene or p-dimethylaminoazobenzene. J Nat/ Cancer lnst 13: 1497, 1952-1953. Sternberg SS, Popper H, Oser BL. et al: Gallbaldder and bile duct adenocarcinoma in dogs after long term feeding of Aramite. Cancer 13: 780, 1960. Akwari OE, Van Heerden JA, Foulk WT, et al: Cancer of the bile ducts associated with ulcerative colitis. Ann Surg 181: 303, 1975. Morowitz DA, Glagov S, Dardal E, et al: Carcinoma of the biliary tract complicating chronic ulcerative colitis. Cancer 27: 356, 1971. Ross AP, Braasch JW, Warren KWz Carcinoma of the proximal bile ducts. Surg Gynecol Obstet 136: 923, 1973. Terblanche J, Saunders SJ, Louw JH: Prolonged palliation in carcinoma of the main hepatic duct junction. Surgery 71: 720, 1972. Crile G: The advantage of bypass operations over radical pancreatoduodenectomy in the treatment of pancreatic carcinoma. Surg Gynecol Obsfet 130: 1048, 1970. Shapiro TM: Adenocarcinoma of the pancreas: a statistical analysis of biliary bypass vs Whipple resection in good risk patients. Ann Surg 182: 715, 1975. Aston SJ, Longmire WP: Pancreaticoducdenal resection: twenty years’ experience. Arch Surg 106: 8 13, 1973. Warren KW, Choe DS, Plaza J, et al: Results of radical resection for periampullary cancer. Ann Surg 181: 534, 1975. Sato T. Saitoh Y. Noto N, et al: Follow-up studies of radical resection for pancreaticoduodenal cancer. Ann Surg 186: 581, 1977. Collins JJ. Craighead JE. Brooks JR: Rationale for total pancreatectomy for carcinoma of the pancreatic head. IV Engl J Med 274: 599, 1966. ReMine WH, Priestley, JT, Judd ES, et al: Total pancreatectomy. Ann Sura 172: 595. 1970. Gotdsmkh ES, Ghosh BC, Huvos AG: Ligation versus implantation of the pancreatic duct after pancbaticoduodenectcmy. Surg Gynecal Obstet 132: 87, 1971. Brunschwig A: A report upon a technique for pancreaticoduodenectomy. Surg Gynecal Obsfet 118: 263, 1964.
The American Journal of Surgery
Extrahepatic
Discussion Ronald K. Tompkins (Los Angeles, CA): Drs. Inouye an,l Whelan have presented a very impressive series of well ev:duat,ed patients with carcinomas of the extrahepatic ducts. Their series differs somewhat from other American reljorts in that almost half their patients were more than seventy years old and many more than half were Oriental. Of interest also was that 47 per cent of their patients had lesions of the distal third of the bile duct, a location where thl chance of surgical cure is greatest. In a series recently reported from our institution (Ann Surg 178: 333, 1973) the frequency of distal third lesions was only 20 per cent of sixty-three cases. Whether these age and racial differences have influenced the anatomic distribution of the lesions or give a clue to their possible causes remains speculative. The survival figures quoted by the authors are about equal to those reported by others. (Slide) Of thirty-four patients we have treated with upper third lesions, five are currently alive. The longest survivor in this group is four ar d a half years after a palliative bypass, demonstrating the slow growth characteristics of some of these tumors. The authors have correctly pointed out that radical pancreatoduodenectomy offers the best chance for cure of those distal third lesions which have not metastasized. T:rey have also reaffirmed the seriousness of pancreatic leaks after Whipple procedures. Although our group has had difficulties with leakage from pancreatojejunostomies, there have also been serious leaks from the oversewn cut end of the pancreas, so we cannot recommend this as an improvement in the technic of the Whipple procedure. We now favor anastomosis of the mucosa of the jejunum to the mucosa of the pancreatic duct when the latter is dilated. When the pancreatic duct is of normal caliber, we invag-, inate the cut end of the pancreas into the jejunum as securely as possible after placing a plastic tube into the pancreatic duct to stent it while healing takes place. (Slide) Of the thirteen patients we have treated with distal third lesions, ten have had Whipple procedures with no operative mortality and a 30 per cent five year survival. Five of t,he thirteen are still alive, two living ten and fifteen years since resection. Finally, the authors have clearly pointed out the great difficulties often encountered in making a definitive diagnosis at operation in these patients. For the past five years we have relied more and more upon operative choledochoscopy to enable us to biopsy the obstruction under direct vision. In addition, we have observed some patients who have had more than one site of tumor within the biliary system, and these patients have been spared a needless radical procedure. We continue to be enthusiastic in the use cjf this new diagnostic tool.
Orville F. Grimes (San Francisco, CA): Three years ago we presented our experience at the University of California, San Francisco before this association with extrahepatic bile duct carcinoma exclusive of the papillary lesions. In general
Volume 136,July 1978
Bile Duct Carcinoma
our resu1t.s were almost identical with those presented herein. These a.re peculiar and frustrating malignancies. They tend toward local spread, enhanced by the actual structural anatomy of the bile ducts. Actually, the ducts are merely thin-walled tubes of fibrous tissue with a few wisps of isolated and scattered muscle fibers. They are also lined with a thin layer of epithelium which extends through the entire wall to form glands on the outer surface of the ducts, thereby allowing malignant cells originating in the mucosa to reach the surface and the periductal regions by direct growth along this glandular system. Furthermore, the outer layers are richly supplied with nerves and lymphatics, and invasion of periductal tissues is common even when the lesion is quite small. (Slide) This specimen appears to be a rather favorable lesion demonstrated by endoscopic retrograde cholangiopancreatography (ERCP), well restricted to the lower portion of the common bile duct. (Slide) Upon laboratory study, perineural invasion directly adjacent to this rather large nerve can be seen. (Slide) A little farther away, there is another nerve which appears to be almost devoured by the metastatic malignancy. Perineural invasion is common and may extend for a considerable distance beyond the limits of the existing lesion. Even without lymph node metastases, and with presumably tumor-free margins of resection, perineural involvement is often the cause of failure. Thomas J. Whelan (closing): We are seeing extrahepatic bile duct cancer most frequently in elderly Japanese patients. This incidence occurs currently in those who were born in Japan and also first generation Japanese. It is going to be very interesting to see whether the prevalence of this disease persists in Japanese people who have lived in Hawaii a longer period of time. In a recent report from Korea (Kim YO, Kim YC, Kim IC, et al: ,l’ersonal communication), there were ninety-six cases of bsiliary carcinoma, sixty-six of which occurred in the extrahepatic bile ducts in one hospital over a ten year period. The Koreans are one of our most, recently migrating groups, and therefore, we may see an upswing on the right side of Dr. Inouye’s bar graph concerning ethnic group incidence. At the Central Regional Hospital in Okinawa, where the University of Hawaii participates in residency training of the house staff, many cases of extrahepatic bile duct carcinoma, demonstrated by use of the percutaneous transhepatic cholangiography, are also noted. Diagno;sis may be difficult. Recently an elderly Japanese patient was referred with the diagnosis of sclerosing cholangitis. This is a diagnosis that enters into the differential diagnosis., but it has been our experience that most of such cases have turned out eventually to be carcinoma of the extrahepatic bile duct system, sclerosing in type. These lesions may spread via perineural lymphatics, or spread directly along the ducts, or the lesions may he multicentric, all of which militate toward a nil prognosis in proximal third lesions.
95
