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Common bile duct stricture as a late complication of upper abdominal radiotherapy
Journal of Hepatology 1994; 20:693-697 Printed in Denmark. All rights reserved Munksgaard. Copenhagen
Copyright © Journal of Hepatology 1994
Journal of Hepatology ISSN 0168-8278
Common bile duct stricture as a late complication of upper abdominal radiotherapy Daniel Cherqui t, L a u r e n t Palazzo 2, Pascal Piedbois 1, Fr6d6ric Charlotte ~, Christophe D u v o u x t, JeanJacques D u r o n 3, Pierre Louis Fagniez I and Dominique Valla 3 IDepartments of Digestive Surgery. Oncology, Hepatology and Pathology H6pital Henri Mondor, CrOteil, 'Endosonography Unit, Paris and 3Departments of Hepatogastroenterology and Surgery, Groupe Hospitalier Piti~-Salp~triOre, Paris, France
(Received 15 September 1992)
We report the cases of two patients who developed symptomatic common bile duct stricture 10 years after upper abdominal radiotherapy for malignant lymphoma. Both patients were in complete remission and presented with marked obstructive jaudice. Endosonography was useful in both cases and showed segmental thickening of the bile duct wall narrowing in the lumen. Both patients underwent surgical exploration, confirming biliary obstruction due to intrinsic wall thickening, and had successful biliary drainage by Roux-en-Y hepatico-jejunostomy. Histological examination of the resected bile duct, in one case, and of a bile duct biopsy, in the other, was consistent with late irradiation injury. We conclude that stricture may be a delayed consequence of radiotherapy applied to normal bile ducts. © Journal of Hepatology. Key words: Endosonography; Obstructive jaundice; Radiotherapy
Bile duct fibrosis due to irradiation has been reported experimentally (1) and in patients who have been treated for bile duct carcinoma (2,3). However, the occurrence of bile duct stricture in patients with normal bile ducts who have received abdominal radiotherapy has not been reported. We report the cases of two patients who developed obstructive jaundice 10 years after upper abdominal irradiation for lymphoma. Evidence is presented that bile duct stricture was the result of radiation injury in both cases. Case Reports Case 1
A 47-year-old man was admitted in May 1990 for obstructive jaundice. Rapidly progressive jaundice had appeared, accompanied by pruritus. There was no fever, chills or abdominal pain. The patient had lost 8 kg in 3 months. In 1979, the patient had been treated for Hodgkin's dis-
ease classified stage II supradiaphragmatic. He was treated with a combination of chemotherapy (CVPP) and radiotherapy of the chest and abdomen. He received 35 grays in 17 fractions over 27 days on a lomboaortic, spleen and mantelet field. Therapy ended in February 1980 and the patient had been in complete remission since that date with full rehabilitation. Physical examination revealed marked jaundice and hepatomegaly. The spleen was not enlarged and no enlarged peripheral lymph nodes were found. Pertinent laboratory data included: white blood cells 4000/mm ~, hemoglobin 12 g/100 ml, platelets 200000/mm 3, prothrombin time 11 s, total bilirubin 320/.tmol/1, direct bilirubin 243 /.tmol/1, alkaline phosphophatase 293 U/I (n< 115), gamma glutamine transpeptidase 112 U/I (n<60), AST 36 IU/1, ALT 89 IU/I. Blood electrolytes, glucose, urea nitrogen and serum creatinine were normal. Serologies for hepatitis A, B and C viruses, cytomegalovirus and human immunodeficiency virus were negative. Upper abdominal ultrasound and CT scan showed dilatation of the intrahepatic bile ducts and the upper corn-
Correspondence to: D. Cherqui M.D., Servicede Chirurgie Digestive, H6pital Henri Mondor, 94000 Cr6teil, France
694
D. CHERQUI et al.
mon bile duct. No lymph nodes or pancreatic tumors were seen. Endosonography (Olympus G F U M 3 echoendoscope) showed a normal pancreas and a 3-cm-long thickening of the common bile duct wall from above the pancreas to above the cystic duct junction. This thickening resulted in complete obstruction of the bile duct lumen (Fig. 1). At laparotomy, the liver was enlarged and cholestatic. The gallbladder was normal. The common bile duct could be palpated in the hepatoduodenal ligament: it was thick, firm and felt like a pencil. The upper common bile duct was dilated with a normally thick wall. Transcystic intraoperative cholangiogram showed a 3-cm-long stenosis at the middle third of the common bile duct which encompassed the cystic duct junction (Fig. 2). Proximal bile ducts were dilated. Small and soft lymph nodes were found in the porta hepatis. The spleen was not enlarged and the rest of the abdomen was normal. Frozen sections
Fig. l. Endosonography in case 1 showing thickening (arrow) of the common bile duct (VBP). Length of the stenosis (between the crosses)=3 cm.
4
a
b
Fig. 2. a. Intraoperative cholanglogram in case I showing a 3-cmlong intrinsic thickening of the bile duct wall occluding its lumen with upstream dilatation, b. Radiotherapy portal fields (between the arrows). The injured bile duct segment is included in the treated volume.
of the bile duct wall and regional lymph nodes showed no evidence of tumor. Cholecystectomy and resection of the common bile duct from above the stenosis to the duodenum were performed followed by a Roux-en-Y hepaticojejunostomy. A liver biopsy was taken. Histologic examination of the resected bile duct showed marked edematous fibrosis which thickened the biliary wall (Fig. 3a). Fibrosis completely replaced the normal muscular cuff of the bile duct and contained a moderate polymorphous inflammatory infiltrate. Dilated capillary vessels and arterioles with an intimal fibrous thickening were present (Figs. 3b and 3c). Biliary epithelium was normal. No tumor was found. The liver biopsy showed major cholestasis and mild fibrosis consistent with chronic bile duct obstruction. Retrospective analysis of films of the volumes covered by external radiation ports showed that the involved segment of bile duct was included in the field (Fig. 2). The postoperative course was uneventful and jaundice rapidly improved. Total bilirubin was 17 pmol/l 1 month after surgery and alkaline phosphatase and gamma glutamine transpeptidase returned to normal within 6 months. Upper abdominal ultrasound performed 6 months after surgery was normal. Two years after surgery, the patient was in excellent condition; he was back to his usual weight and had returned to work. Case 2 A 53 year-old man was admitted in July 1990 for obstructive jaundice which had appeared progressively over the preceding 2 weeks. There was no pruritis, fever, chills or abdominal pain and general condition was good with no weight loss. The patient had had a low-grade splenic lymphoma in 1980 treated by splenectomy and a combination of chemotherapy (MOPP) and radiotherapy. The patient received 40 grays on a lomboaortic field. He was in complete remission until 1985, when a monoclonal IgA Kappa peak was found in the serum associated with mild bone marrow infiltration by lymphoma. He was treated by chloraminophene and steroids for 6 months. Since then the patient has been in complete clinical and biological remission. Physical examination was unremarkable except for jaundice. Pertinent laboratory data included: white blood cells 9900/mm 3, hemoglobin 10.5 g/100 ml, platelets 652000/mm 3, prothrombin time 12 s, total bilirubin 480 /.tmol/l, direct bilirubin 404 pmol/l, alkaline phosphophatase 557 U/1 (n
COMMON BILE DUCT STRICTURE
:-u-,%
-
695
' . . . . .
-
"
-
Fig. 3. Histological studies in case 1. a. Bile duct wall thickened by marked edematous fibrosis and normal biliary epithelium, b. Dilated capillaries in the bile duct wall. c. Artery with intimal fibrous thickening. megalovirus and human immunodeficiency virus were negative. Upper abdominal ultrasound and CT scan showed markedly dilated intrahepatic bile ducts and upper common bile duct. N o lymph nodes were seen, nor pancreatic tumor. Endosonography (Olympus G F U M 3 echoendoscope) showed a normal pancreas and a 2-cm-long sten-
Fig. 4. Endosonography in case 2 showing thickening (arrow) of the bile duct wall (VBP). (CYS : cystic duct, TP : portal vein).
osis of the c o m m o n bile duct in its retropancreatic segment. The bile duct wall was thickened on the stenotic segment and the wall measured 3 mm. The bile duct was dilated above the stricture with a diameter of 13 mm (Fig. 4). At laparotomy, the liver was enlarged and cholestatic. The gallbladder was not enlarged. The middle common bile duct was hard and infiltrated. The upper c o m m o n bile duct was enlarged with a normal consistency of its wall. Small and soft lymph nodes were found in the porta hepatis. The rest of the abdomen was normal. Intraoperative cholangiogram, obtained by direct puncture of the c o m m o n bile duct, showed dilatation of the intra- and extra-hepatic bile ducts above a complete obstruction of the c o m m o n bile duct in its middle segment (Fig. 5). Frozen sections of the bile duct wall and regional lymph nodes showed no evidence of tumor. Biopsy of the common bile duct at the site of the stricture was taken for complementary histological examination. Cholecystectomy and biliary diversion by a Roux-en-Y hepaticojejunostomy were performed. A liver biopsy was taken. Histologic examination of the bile duct biopsy showed fibrous tissue with mild mononuclear cell infltration. No tumor was seen. The liver biopsy showed cholestasis and
696
D. CHERQUI et al.
, a
i b
Fig. 5. a. Intraoperative cholanglogram in case 2 showing complete obstruction of the distal common bile duct. b. Radiotherapy portal fields (between the arrows). The injured bile duct segment is included in the treated volume.
mild fibrosis consistent with chronic obstruction of the bile duct. Retrospective analysis of films of volumes covered by external radiation ports showed that the involved segment of bile duct was included in the field of irradiation (Fig. 5). The postoperative course was uneventful and jaundice rapidly improved. Total bilirubin was 16/lmol/1 and alkaline phosphatase 166 U/l, 1 month after surgery. Two years after surgery, the patient was in excellent condition and liver tests were within the normal range. Discussion The two cases reported here are very similar in many respects, with evidence that biliary obstruction was the result of late radiation injury. Both patients had been treated for a malignant lymphoma 10 years earlier and received radiotherapy in fields encompassing the porta hepatis as shown by retrospective analysis of the volume films. Chemotherapy was associated with radiotherapy in both cases. Both patients were in complete remission and presented with isolated obstructive jaundice due to a common bile stricture in its middle third. At surgery, the bile duct lesion appeared as a thickening of the wall without evidence of tumor. Histologically, normal epithelium surrounded by fibrosis, edema and mild polymorphous infiltration, was observed, and, in one case, vasculitis was present. In the patients in this study, other diagnoses were considered before surgery including recurrent lymphoma, bile duct carcinoma, infectious stricture and sclerosing cholangitis. Biliary obstruction by lymphoma has been reported and is usually the result of compressive lymph
nodes in the porta hepatis or, of extension of gastroduodenal or pancreatic lymphoma (4). Occasionally, intrinsic lymphomatous infiltration of the bile duct may occur (5). In our patients, obstruction by recurrent lymphoma was excluded by the absence of lymph nodes and by histologic study of the bile duct wall and liver biopsy. Patients with a past history of malignancy treated by chemotherapy and radiotherapy have an increased risk of developing a second malignancy (6). Bile duct carcinoma was possible (7) but was excluded in the patients in this study by histological examination of the stricture. Endosonography indicated localized sclerosing cholangitis by showing a segmental thickening of the bile duct wall in both cases. However, in our patients the clinical setting as well as the cholangiographic and liver histological patterns excluded this diagnosis. Finally, bile duct stenosis due to cryptosporidium or cytomegalovirus has been reported in patients with the acquired immune deficiency syndrome (8), but human immunodeficiency virus serology was negative in both patients. Endosonography excluded compressive lymph nodes and gave a precise description of extrahepatic bile duct wall thickening with reduction of the lumen, and allowed surgery without preoperative cholangiography. Patients with obstructive jaundice are usually explored by ultrasound and/or CT scan followed by direct cholangiography obtained endoscopically or percutaneously. These latter two methods are invasive and carry.a risk of morbidity. Endosonography is minimally invasive with no risk of morbidity. We believe that endosonography is very useful in the differential diagnosis of obstructive jaundice (9,10) and may be used instead of preoperative cholangiography in selected cases. It has been shown that normal dogs subjected to intraoperative irradiation develop bile duct fibrosis (1). Several cases of residual bile duct strictures after radiation therapy for bile duct carcinoma have been reported (2,3). However, in those cases, biliary strictures were located at the site of the tumor, and residual or recurrent cancer could not be excluded. In the cases in this study, the presence of fibrosis alone was substantiated by surgical specimens, especially in case 1, where the strictured common bile duct was resected. Complications of radiation therapy include acute and delayed injuries. The toxicity of radiotherapy is the result of cellular and microvascular injuries (11,12). Acute lesions predominantly affect tissues with rapid renewal such as hematopoietic tissue and epithelium, whereas later lesions are usually due to injuries to the vascular endothelium and connective tissue (12). This leads to progressive microvasculitis and eventually to tissue hypoxia. Collagen deposits cause fibrosis and inhibit tissue repair. Late complications are usually long-term processes. For ex-
COMMON BILE DUCT STRICTURE ample, it is well established that chronic radiation enteritis often becomes s y m p t o m a t i c several years after irradiation (12). There was a long symptom-free period (10 years) in both cases in this study. It seems that vasculitis progresses a u t o n o m o u s l y until tissue damage becomes symptomatic. In the first case in this study, segmental stricture o f the middle portion o f the c o m m o n bile duct was observed, while the rest o f the duct was normal. It has been shown that this middle segment has a p o o r e r arterial supply than the upper and lower segments o f the duct (13), which could result in a higher susceptibility o f this area to the consequences o f radiation-induced vasculitis. A n o t h e r theory is that subclinical injury m a y become overt when cardiovascular disease such as congestive heart failure, hypertension or arteriosclerosis occurs and increases hypoxia above a critical level (12). This, however, was not the case in the two patients in this study. R a d i a t i o n effects can be enhanced by chemotherapy, especially doxorubicin and fluoro-uracil (14). Although these drugs were not used in our patients, they both received chemotherapy by CVPP and M O P P protocols, respectively, which might have increased radiation toxicity. Histologic features of late radiation injury are fibrosis and vascular lesions including capillary dilatation and arteriolopathy (11). The most typical arterial lesion is foam cell intimal deposition. Intimal fibrosis, which was present in case 1, although less specific, is more c o m m o n l y observed (11). Fibrosis was present in both cases associated with vasculitis in case 1. Histologic study in case 1 is characteristic of chronic radiation injury. We conclude that bile duct stricture may be a late complication o f upper a b d o m i n a l r a d i o t h e r a p y in patients with previously normal bile ducts.
697
References 1. Sindelar WF, Tepper J, Travis EL. Tolerance of bile duct to intraoperative irradiation. Surgery 1982; 92: 533-40. 2. Martenson JA, Gunderson LL, Buskirk SJ, et al. Hepatic duct stricture after radical radiation therapy for biliary cancer: recurrence or fibrosis.'?Mayo Clin Proc 1986; 61: 530-6. 3. Green N, Mikkelsen WP, Kernen JA. Cancer of the common hepatic bile duct. Palliative radiotherapy. Radiology 1973; 109: 687-9. 4. Feller E, Schiffman FJ. Extrahepatic biliary obstruction by lymphoma. Arch Surg 1990; 125: 1507-9. 5. Nguyen GK. Primary extranodal non-Hodgkin's lymphoma of the extrahepatic bile duct : report of a case. Cancer 1982; 50: 2218-22. 6. Tucker MA, Coleman CN, Cox RS, Varghese A, Rosenberg SA. Risk of second cancer after treatment for Hodgkin's disease. N Engl J Med 1988; 318: 76-81. 7. Zarrabi MH, Rosner F. Second neoplasms in Hodgkin's disesase: current controversies. Hematology/Oncology Clinics of North America. Hodgkin's disease. Philadelphia: WB Saunders 1989; 3: 303-17. 8. Roulot D, Valla D, Brun-Vezinet F, et al. Cholangitis in the acquired immunodeficiency syndrome: report of two cases and review of the literature. Gut 1987; 28: 1653-60. 9. Amouyal P, Palazzo L, Amouyal G, et al. Endosonography: a promising method for diagnosis of extrahepatic cholestasis. Lancet 1989; ii: 1195-8. 10. Tio TL, Cheng J, Wijers OB, Sars PRA, Tytgat GNJ. Endosonographic TNM staging of extrahepatic bile duct cancer: comparison with pathological staging. Gastroenterology 1991; 100: 1351-61. I1. Fajardo LF, Berthrong M. Radiation injury in surgical pathology. Part I. Am J Surg Path 1978; 2: 159-99. 12. De Cosse J J, Rhodes RS, Wentz WB, Regan JW, Dworken H J, Holden WD. The natural history and management of radiationinduced injury of the gastrointestinal tract. Ann Surg 1970; 170: 369-75. 13. Terblanche J, Allison HF, Northover JMA. An ischemic basis for biliary strictures. Surgery 1983; 94: 52-7. 14. Vokes EE, Weichselbaum RR. Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 1990; 8; 911-34.
Copyright © Journal of Hepatology 1994
Journal of Hepatology ISSN 0168-8278
Common bile duct stricture as a late complication of upper abdominal radiotherapy Daniel Cherqui t, L a u r e n t Palazzo 2, Pascal Piedbois 1, Fr6d6ric Charlotte ~, Christophe D u v o u x t, JeanJacques D u r o n 3, Pierre Louis Fagniez I and Dominique Valla 3 IDepartments of Digestive Surgery. Oncology, Hepatology and Pathology H6pital Henri Mondor, CrOteil, 'Endosonography Unit, Paris and 3Departments of Hepatogastroenterology and Surgery, Groupe Hospitalier Piti~-Salp~triOre, Paris, France
(Received 15 September 1992)
We report the cases of two patients who developed symptomatic common bile duct stricture 10 years after upper abdominal radiotherapy for malignant lymphoma. Both patients were in complete remission and presented with marked obstructive jaudice. Endosonography was useful in both cases and showed segmental thickening of the bile duct wall narrowing in the lumen. Both patients underwent surgical exploration, confirming biliary obstruction due to intrinsic wall thickening, and had successful biliary drainage by Roux-en-Y hepatico-jejunostomy. Histological examination of the resected bile duct, in one case, and of a bile duct biopsy, in the other, was consistent with late irradiation injury. We conclude that stricture may be a delayed consequence of radiotherapy applied to normal bile ducts. © Journal of Hepatology. Key words: Endosonography; Obstructive jaundice; Radiotherapy
Bile duct fibrosis due to irradiation has been reported experimentally (1) and in patients who have been treated for bile duct carcinoma (2,3). However, the occurrence of bile duct stricture in patients with normal bile ducts who have received abdominal radiotherapy has not been reported. We report the cases of two patients who developed obstructive jaundice 10 years after upper abdominal irradiation for lymphoma. Evidence is presented that bile duct stricture was the result of radiation injury in both cases. Case Reports Case 1
A 47-year-old man was admitted in May 1990 for obstructive jaundice. Rapidly progressive jaundice had appeared, accompanied by pruritus. There was no fever, chills or abdominal pain. The patient had lost 8 kg in 3 months. In 1979, the patient had been treated for Hodgkin's dis-
ease classified stage II supradiaphragmatic. He was treated with a combination of chemotherapy (CVPP) and radiotherapy of the chest and abdomen. He received 35 grays in 17 fractions over 27 days on a lomboaortic, spleen and mantelet field. Therapy ended in February 1980 and the patient had been in complete remission since that date with full rehabilitation. Physical examination revealed marked jaundice and hepatomegaly. The spleen was not enlarged and no enlarged peripheral lymph nodes were found. Pertinent laboratory data included: white blood cells 4000/mm ~, hemoglobin 12 g/100 ml, platelets 200000/mm 3, prothrombin time 11 s, total bilirubin 320/.tmol/1, direct bilirubin 243 /.tmol/1, alkaline phosphophatase 293 U/I (n< 115), gamma glutamine transpeptidase 112 U/I (n<60), AST 36 IU/1, ALT 89 IU/I. Blood electrolytes, glucose, urea nitrogen and serum creatinine were normal. Serologies for hepatitis A, B and C viruses, cytomegalovirus and human immunodeficiency virus were negative. Upper abdominal ultrasound and CT scan showed dilatation of the intrahepatic bile ducts and the upper corn-
Correspondence to: D. Cherqui M.D., Servicede Chirurgie Digestive, H6pital Henri Mondor, 94000 Cr6teil, France
694
D. CHERQUI et al.
mon bile duct. No lymph nodes or pancreatic tumors were seen. Endosonography (Olympus G F U M 3 echoendoscope) showed a normal pancreas and a 3-cm-long thickening of the common bile duct wall from above the pancreas to above the cystic duct junction. This thickening resulted in complete obstruction of the bile duct lumen (Fig. 1). At laparotomy, the liver was enlarged and cholestatic. The gallbladder was normal. The common bile duct could be palpated in the hepatoduodenal ligament: it was thick, firm and felt like a pencil. The upper common bile duct was dilated with a normally thick wall. Transcystic intraoperative cholangiogram showed a 3-cm-long stenosis at the middle third of the common bile duct which encompassed the cystic duct junction (Fig. 2). Proximal bile ducts were dilated. Small and soft lymph nodes were found in the porta hepatis. The spleen was not enlarged and the rest of the abdomen was normal. Frozen sections
Fig. l. Endosonography in case 1 showing thickening (arrow) of the common bile duct (VBP). Length of the stenosis (between the crosses)=3 cm.
4
a
b
Fig. 2. a. Intraoperative cholanglogram in case I showing a 3-cmlong intrinsic thickening of the bile duct wall occluding its lumen with upstream dilatation, b. Radiotherapy portal fields (between the arrows). The injured bile duct segment is included in the treated volume.
of the bile duct wall and regional lymph nodes showed no evidence of tumor. Cholecystectomy and resection of the common bile duct from above the stenosis to the duodenum were performed followed by a Roux-en-Y hepaticojejunostomy. A liver biopsy was taken. Histologic examination of the resected bile duct showed marked edematous fibrosis which thickened the biliary wall (Fig. 3a). Fibrosis completely replaced the normal muscular cuff of the bile duct and contained a moderate polymorphous inflammatory infiltrate. Dilated capillary vessels and arterioles with an intimal fibrous thickening were present (Figs. 3b and 3c). Biliary epithelium was normal. No tumor was found. The liver biopsy showed major cholestasis and mild fibrosis consistent with chronic bile duct obstruction. Retrospective analysis of films of the volumes covered by external radiation ports showed that the involved segment of bile duct was included in the field (Fig. 2). The postoperative course was uneventful and jaundice rapidly improved. Total bilirubin was 17 pmol/l 1 month after surgery and alkaline phosphatase and gamma glutamine transpeptidase returned to normal within 6 months. Upper abdominal ultrasound performed 6 months after surgery was normal. Two years after surgery, the patient was in excellent condition; he was back to his usual weight and had returned to work. Case 2 A 53 year-old man was admitted in July 1990 for obstructive jaundice which had appeared progressively over the preceding 2 weeks. There was no pruritis, fever, chills or abdominal pain and general condition was good with no weight loss. The patient had had a low-grade splenic lymphoma in 1980 treated by splenectomy and a combination of chemotherapy (MOPP) and radiotherapy. The patient received 40 grays on a lomboaortic field. He was in complete remission until 1985, when a monoclonal IgA Kappa peak was found in the serum associated with mild bone marrow infiltration by lymphoma. He was treated by chloraminophene and steroids for 6 months. Since then the patient has been in complete clinical and biological remission. Physical examination was unremarkable except for jaundice. Pertinent laboratory data included: white blood cells 9900/mm 3, hemoglobin 10.5 g/100 ml, platelets 652000/mm 3, prothrombin time 12 s, total bilirubin 480 /.tmol/l, direct bilirubin 404 pmol/l, alkaline phosphophatase 557 U/1 (n
COMMON BILE DUCT STRICTURE
:-u-,%
-
695
' . . . . .
-
"
-
Fig. 3. Histological studies in case 1. a. Bile duct wall thickened by marked edematous fibrosis and normal biliary epithelium, b. Dilated capillaries in the bile duct wall. c. Artery with intimal fibrous thickening. megalovirus and human immunodeficiency virus were negative. Upper abdominal ultrasound and CT scan showed markedly dilated intrahepatic bile ducts and upper common bile duct. N o lymph nodes were seen, nor pancreatic tumor. Endosonography (Olympus G F U M 3 echoendoscope) showed a normal pancreas and a 2-cm-long sten-
Fig. 4. Endosonography in case 2 showing thickening (arrow) of the bile duct wall (VBP). (CYS : cystic duct, TP : portal vein).
osis of the c o m m o n bile duct in its retropancreatic segment. The bile duct wall was thickened on the stenotic segment and the wall measured 3 mm. The bile duct was dilated above the stricture with a diameter of 13 mm (Fig. 4). At laparotomy, the liver was enlarged and cholestatic. The gallbladder was not enlarged. The middle common bile duct was hard and infiltrated. The upper c o m m o n bile duct was enlarged with a normal consistency of its wall. Small and soft lymph nodes were found in the porta hepatis. The rest of the abdomen was normal. Intraoperative cholangiogram, obtained by direct puncture of the c o m m o n bile duct, showed dilatation of the intra- and extra-hepatic bile ducts above a complete obstruction of the c o m m o n bile duct in its middle segment (Fig. 5). Frozen sections of the bile duct wall and regional lymph nodes showed no evidence of tumor. Biopsy of the common bile duct at the site of the stricture was taken for complementary histological examination. Cholecystectomy and biliary diversion by a Roux-en-Y hepaticojejunostomy were performed. A liver biopsy was taken. Histologic examination of the bile duct biopsy showed fibrous tissue with mild mononuclear cell infltration. No tumor was seen. The liver biopsy showed cholestasis and
696
D. CHERQUI et al.
, a
i b
Fig. 5. a. Intraoperative cholanglogram in case 2 showing complete obstruction of the distal common bile duct. b. Radiotherapy portal fields (between the arrows). The injured bile duct segment is included in the treated volume.
mild fibrosis consistent with chronic obstruction of the bile duct. Retrospective analysis of films of volumes covered by external radiation ports showed that the involved segment of bile duct was included in the field of irradiation (Fig. 5). The postoperative course was uneventful and jaundice rapidly improved. Total bilirubin was 16/lmol/1 and alkaline phosphatase 166 U/l, 1 month after surgery. Two years after surgery, the patient was in excellent condition and liver tests were within the normal range. Discussion The two cases reported here are very similar in many respects, with evidence that biliary obstruction was the result of late radiation injury. Both patients had been treated for a malignant lymphoma 10 years earlier and received radiotherapy in fields encompassing the porta hepatis as shown by retrospective analysis of the volume films. Chemotherapy was associated with radiotherapy in both cases. Both patients were in complete remission and presented with isolated obstructive jaundice due to a common bile stricture in its middle third. At surgery, the bile duct lesion appeared as a thickening of the wall without evidence of tumor. Histologically, normal epithelium surrounded by fibrosis, edema and mild polymorphous infiltration, was observed, and, in one case, vasculitis was present. In the patients in this study, other diagnoses were considered before surgery including recurrent lymphoma, bile duct carcinoma, infectious stricture and sclerosing cholangitis. Biliary obstruction by lymphoma has been reported and is usually the result of compressive lymph
nodes in the porta hepatis or, of extension of gastroduodenal or pancreatic lymphoma (4). Occasionally, intrinsic lymphomatous infiltration of the bile duct may occur (5). In our patients, obstruction by recurrent lymphoma was excluded by the absence of lymph nodes and by histologic study of the bile duct wall and liver biopsy. Patients with a past history of malignancy treated by chemotherapy and radiotherapy have an increased risk of developing a second malignancy (6). Bile duct carcinoma was possible (7) but was excluded in the patients in this study by histological examination of the stricture. Endosonography indicated localized sclerosing cholangitis by showing a segmental thickening of the bile duct wall in both cases. However, in our patients the clinical setting as well as the cholangiographic and liver histological patterns excluded this diagnosis. Finally, bile duct stenosis due to cryptosporidium or cytomegalovirus has been reported in patients with the acquired immune deficiency syndrome (8), but human immunodeficiency virus serology was negative in both patients. Endosonography excluded compressive lymph nodes and gave a precise description of extrahepatic bile duct wall thickening with reduction of the lumen, and allowed surgery without preoperative cholangiography. Patients with obstructive jaundice are usually explored by ultrasound and/or CT scan followed by direct cholangiography obtained endoscopically or percutaneously. These latter two methods are invasive and carry.a risk of morbidity. Endosonography is minimally invasive with no risk of morbidity. We believe that endosonography is very useful in the differential diagnosis of obstructive jaundice (9,10) and may be used instead of preoperative cholangiography in selected cases. It has been shown that normal dogs subjected to intraoperative irradiation develop bile duct fibrosis (1). Several cases of residual bile duct strictures after radiation therapy for bile duct carcinoma have been reported (2,3). However, in those cases, biliary strictures were located at the site of the tumor, and residual or recurrent cancer could not be excluded. In the cases in this study, the presence of fibrosis alone was substantiated by surgical specimens, especially in case 1, where the strictured common bile duct was resected. Complications of radiation therapy include acute and delayed injuries. The toxicity of radiotherapy is the result of cellular and microvascular injuries (11,12). Acute lesions predominantly affect tissues with rapid renewal such as hematopoietic tissue and epithelium, whereas later lesions are usually due to injuries to the vascular endothelium and connective tissue (12). This leads to progressive microvasculitis and eventually to tissue hypoxia. Collagen deposits cause fibrosis and inhibit tissue repair. Late complications are usually long-term processes. For ex-
COMMON BILE DUCT STRICTURE ample, it is well established that chronic radiation enteritis often becomes s y m p t o m a t i c several years after irradiation (12). There was a long symptom-free period (10 years) in both cases in this study. It seems that vasculitis progresses a u t o n o m o u s l y until tissue damage becomes symptomatic. In the first case in this study, segmental stricture o f the middle portion o f the c o m m o n bile duct was observed, while the rest o f the duct was normal. It has been shown that this middle segment has a p o o r e r arterial supply than the upper and lower segments o f the duct (13), which could result in a higher susceptibility o f this area to the consequences o f radiation-induced vasculitis. A n o t h e r theory is that subclinical injury m a y become overt when cardiovascular disease such as congestive heart failure, hypertension or arteriosclerosis occurs and increases hypoxia above a critical level (12). This, however, was not the case in the two patients in this study. R a d i a t i o n effects can be enhanced by chemotherapy, especially doxorubicin and fluoro-uracil (14). Although these drugs were not used in our patients, they both received chemotherapy by CVPP and M O P P protocols, respectively, which might have increased radiation toxicity. Histologic features of late radiation injury are fibrosis and vascular lesions including capillary dilatation and arteriolopathy (11). The most typical arterial lesion is foam cell intimal deposition. Intimal fibrosis, which was present in case 1, although less specific, is more c o m m o n l y observed (11). Fibrosis was present in both cases associated with vasculitis in case 1. Histologic study in case 1 is characteristic of chronic radiation injury. We conclude that bile duct stricture may be a late complication o f upper a b d o m i n a l r a d i o t h e r a p y in patients with previously normal bile ducts.
697
References 1. Sindelar WF, Tepper J, Travis EL. Tolerance of bile duct to intraoperative irradiation. Surgery 1982; 92: 533-40. 2. Martenson JA, Gunderson LL, Buskirk SJ, et al. Hepatic duct stricture after radical radiation therapy for biliary cancer: recurrence or fibrosis.'?Mayo Clin Proc 1986; 61: 530-6. 3. Green N, Mikkelsen WP, Kernen JA. Cancer of the common hepatic bile duct. Palliative radiotherapy. Radiology 1973; 109: 687-9. 4. Feller E, Schiffman FJ. Extrahepatic biliary obstruction by lymphoma. Arch Surg 1990; 125: 1507-9. 5. Nguyen GK. Primary extranodal non-Hodgkin's lymphoma of the extrahepatic bile duct : report of a case. Cancer 1982; 50: 2218-22. 6. Tucker MA, Coleman CN, Cox RS, Varghese A, Rosenberg SA. Risk of second cancer after treatment for Hodgkin's disease. N Engl J Med 1988; 318: 76-81. 7. Zarrabi MH, Rosner F. Second neoplasms in Hodgkin's disesase: current controversies. Hematology/Oncology Clinics of North America. Hodgkin's disease. Philadelphia: WB Saunders 1989; 3: 303-17. 8. Roulot D, Valla D, Brun-Vezinet F, et al. Cholangitis in the acquired immunodeficiency syndrome: report of two cases and review of the literature. Gut 1987; 28: 1653-60. 9. Amouyal P, Palazzo L, Amouyal G, et al. Endosonography: a promising method for diagnosis of extrahepatic cholestasis. Lancet 1989; ii: 1195-8. 10. Tio TL, Cheng J, Wijers OB, Sars PRA, Tytgat GNJ. Endosonographic TNM staging of extrahepatic bile duct cancer: comparison with pathological staging. Gastroenterology 1991; 100: 1351-61. I1. Fajardo LF, Berthrong M. Radiation injury in surgical pathology. Part I. Am J Surg Path 1978; 2: 159-99. 12. De Cosse J J, Rhodes RS, Wentz WB, Regan JW, Dworken H J, Holden WD. The natural history and management of radiationinduced injury of the gastrointestinal tract. Ann Surg 1970; 170: 369-75. 13. Terblanche J, Allison HF, Northover JMA. An ischemic basis for biliary strictures. Surgery 1983; 94: 52-7. 14. Vokes EE, Weichselbaum RR. Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 1990; 8; 911-34.