1112 9 ,
The Association Between Cholangiocarcinoma and Hereditary Nonpolyposis Colorectal Carcinoma 1.-P. Mecklin, MD,* H. 1.Jarvinen, MD,t and M. Virolainen, MD$
Eighteen patients with a biliopancreatic carcinoma in 15 different cancer famiIy syndrome (CFS) families were studied. Only families with three or more first-degreerelatives with colorectal carcinoma were included, and other characteristics of CFS were required in at least two cases. In 14 patients, the histologic specimen was available for reevaluation. In 11 (79%), the tumor was confirmed as a carcinoma of the biliary tract or papilla of Vater. In three (21%),carcinoma of the pancreas was the most probable alternative. In all- four patients without histologic reevaluation, the diagnosis had been carcinoma of the biliary tract. This study suggests that carcinoma of the biliary tract or papilla of Vater k associated more commonly with CFS than with carcinoma of the pancreas. In this respect, CFS resembles familial adenomatosis coli, in which this association previously has been established. Cancer 1992; 691112-1114.
Hereditary nonpolyposis colorectal cancer (HNPCC), also known as cancer family syndrome (CFS), seems to be the most common verifiable risk factor of colorectal carcinoma and includes 4% to 6% of all colorectal carcinoma cases.lZ2 The most common extracolonic tumors associating with CFS are endometrial and gastric carcinomas.'~~ Carcinoma of the pancreas also has been observed in families with CFS,4,5and one family with HNPCC and three family members affected by pancreatic carcinoma recently was reported.6However, details of histologic documentation have not been included in these publications. We analyzed the 18 biliopancreatic carcinomas found in 40 verified CFS families in the Finnish CFS registry in an attempt to find the exact origin
From the *Department of Surgery, Jyvaskyla Central Hospital, Jyvaskyla, the tSecond Department of Surgery, Helsinki University Central Hospital, Helsinki, and the $Department of Pathology, Helsinki University, Finland. Supported by the Finnish Cancer Foundation and the Finnish Foundation for Gastroenterology, Helsinki. Address for reprints: J.-P. Mecklin, MD, Jyvaskyla Central Hospital, 40620 Jyvaskyla, Finland. Accepted for publication November 15, 1991.
of the tumors and to evaluate possible associations with the hereditary trait. Patients and Methods
Families with HNPCC have been studied systematically by the Finnish CFS registry since 1983. Within 6 years, almost 100 different cancer families have been filed at the registry. Forty fully examined families were definite CFS families when the minimum criterion was at least three first-degree relatives with colorectal carcinoma with at least two such members expressing one of the following features typical of CFS: (1)a first diagnosis at age younger than 50 years, (2) multiple primary colorectal carcinomas (synchronous or metachronous), and (3) the occurrence of additional primary carcinomas. The total number of affected family members in these 40 families was 315 (174 men and 141 women; mean age, 47.9 years), with a total of 472 separate tumors or diffuse malignant lesions. Details of these families and the overall tumor spectrum (Table 1)have been published el~ewhere.~ Eighteen patients (5.7%) had a primary biliopancreatic carcinoma, which was the third most common extracolonic malignancy next to endometrial and gastric cancer. The clinical data and histologic specimens, when available, of these 18 patients were obtained for reevaluation. Complete hospital records and histologic specimens were available in 14 patients. In two patients, hospital records and the original pathologic report were obtainable, but in two, the death certificate was the only document available. Results
The mean age of the 18 patients studied (10 men and 8 women) at the time biliopancreatic carcinoma was diagnosed was 55.7 years (range, 29 to 80 years). The mean age was 54 years in those nine patients in whom biliopancreatic carcinoma was the only malignant lesion observed; it was 65 years in patients with multiple
Cholangiocarcinoma and Colorectal CA/Mecklin et al. Table 1. Tumor Distribution of 315 Patients in 40 Families With Hereditary Nonpolyposis Colorectal Cancer Tumor No.(%) Colorectum Uterus Stomach Biliopancreatic Urinary tract Breast Sarcomas Skin Small bowel Lung Ovary Other NUD Total NUD: Tumor location not specified. * l'ercentaee urouortion in all uatientshn women.
tumors. Multiple (two to eight) metachronous cancers had been diagnosed in nine (50%) patients, with one or multiple colorectal carcinomas in eight of them (Table 2). The histologic specimen was reevaluated in 14 patients (Table 2, Patients l to 14). In l l (79%) of these (Patients 1 to ll), the tumor was an extrapancreatic adenocarcinoma, originating from the biliary tract in 7 (intrahepatic, one; extrahepatic, six) and from the pa-
1113
pilla of Vater in 4. Carcinoma of the pancreas was the most likely site of the tumor in three patients (12 to 14). In four patients, the histologic specimen were not available for reevaluation (Table 2, Patients 15 to 18).In two patients, the diagnosis of intrahepatic cholangiocarcinoma was based on biopsy and relevant radiologic examinations excluding the possibility of metastases. In one of these, the patient underwent surgery, and the pancreas also was examined during the operation. In two patients, the death certificate was the only available data (Table 2, Patients 15 to 16), and therefore it was impossible to c o n b the diagnosis retrospectively. The overall prognosis was poor. The tumor was resected with curative intent in one patient only, and none of the patients survived longer than 2 years after the diagnosis of biliopancreatic carcinoma was made, In seven patients, the stomach and duodenum had been examined properly to exclude gastric and duodenal polyps. In four, this was confirmed during the autopsy; in one, by gastroscopy; and in one, by a barium meal. For the seventh patient, a pancreaticoduodenectomy was done for ampullary carcinoma. No polyps were observed in the surgical specimen. Discussion
In our study, several findings indicate indirectly that carcinoma of the biliary tract is associated with the HNPCC syndrome. One half of the patients were indis-
Table 2. Sex, Age, Year of Diagnosis, Location of Biliopancreatic Carcinomas, and Distribution of Metachronous Tumors of Studv Subiects Patient no.
Sex/age (yr)
Year
Basis of diagnosis
Location
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
M/64 M/38 F/40 F/54 M/56 F/67 F/72 F/58 M/63 F/67 M/77 M/52 M/58 M/74 F/80 M/54 M/29 F/72
1982 1957 1984 1983 1986 1985 1985 1981 1983 1982 1987 1983 1986 1988 1957 1951 1959 1972
Biopsy Operation Operation Operation Operation Operation Operation Operation Operation Operation Operation Autopsy Autopsy Autopsy Death certificate Death certificate Operation Biopsy
Intrahepatic Common bile duct Common bile duct Common bile duct Common bile duct Common bile duct Common bile duct Ampulla of Vater Ampulla of Vater Ampulla of Vater Ampulla of Vater Pancreas Pancreas Pancreas Common bile duct Intrahepatic Intrahepatic Intrahepatic
Colon 36, ovary 45, uterus 46, stomach 50, colon and rectum 57, skin 59, suprarenal adenoma 65. t Colon 57, colon X 2 60, colon X 2 64, rectum 73, skin 75.
Metachronous tumors
Colon Uterus, colon
Colon 8 different* 7 differentt Colon X 2, sarcoma Colon X 2, rectum Colon X 2, stomach
Uterus
1114
CANCER March 2,1992, Volume 69, No. 5
putably ones with HNPCC and multiple malignant lesions. Biliopancreatic carcinoma was the fourth most common tumor in the families with HNPCC after colorectal, endometrial, and gastric carcinoma. Most of the tumors were biliary tract or ampullary carcinomas. In only three instances (17%)was the pancreas the most probable origin of the tumor, and no case of carcinoma of the gall bladder was observed. In the general Finnish population, biliopancreaticcarcinoma is the ninth most common malignant lesion, and most of these tumors in both sexes originate in the pancreas. The proportion of extrapancreatic carcinomas is only 40% in women and 20% in men.' An association between pancreatic carcinoma and HNPCC has been suggested in single-family report^.^,^ In addition, carcinoma of the biliary tract and duodenum has been observed in two members of a well-documented family with HNPCC reported previously,4 but the histologic details of biliopancreatictumors were usually missing in family reports of HNPCC kindreds. Interestingly, biliary and ampullary tumors are common in patients with familial adenomatous polyposis of the colon (FAP),*-" which can be seen as a counterpart to HNPCC from a genetic point of view. However, pancreatic carcinoma has not been reported, more frequently in FAP than in the general population.8 Our observations of 40 families with HNPCC and 14 biliary tract or ampullary carcinomas suggest the presence of a similar tumor spectrum in HNPCC and FAP." In FAP, however, there is much evidence that carcinomas of the upper gastrointestinal tract arise from preexisting duodenal or juxtapapillary adenomas?" although no such premalignant lesions were detected in our patients, even though seven of them were examined in this respect. Nonetheless, the topographic analogy in upper gastrointestinal tumors between HNPCC and FAP may reflect a similar or closely related pathogenic mechanism, e.g., a metabolic alteration in bile acid synthesis. The altered metabolites may act as tumorpromoting factors, possibly through the adenoma-carcinoma seq~ence.~~" Our results indicate the need for a more accurate diagnostic workup for extracolonic carcinomas in patients with HNPCC to clarify the real tumor spectrum of this syndrome. A preoperative gastroscopy and abdominal ultrasound sonography is recommended for such patients while waiting for surgery on colonic or other abdominal carcinomas. If abnormal findings are observed in the biliary tract preoperatively or peropera-
tively, needle cholangiography should be done. Six of our patients had been operated on within a few years before the carcinoma of the biliary tract was diagnosed. Therefore, a systematic and careful exploration of the biliary tract may detect an asymptomatic biliary tract tumor as has been observed in patients with FAP." In conclusion, tumors of the biliary tract and ampulla of Vater seem to belong to the tumor spectrum of HNPCC rather than to that of pancreatic carcinoma. Colorectal and endometrial cancers are by far the most common tumors of this hereditary syndrome and justify screening of asymptomatic family members. However, the association of bile duct tumors with HNPCC becomes important in the treatment and follow-up of affected patients. It is suggested that upper gastrointestinal tract endoscopy, abdominal ultrasound sonography, and liver function tests should be a part of the diagnostic workup and follow-up program of patients with HNPCC and colorectal or endometrial tumors. References 1. Lynch HT, Lanspa SJ, Boman BM et al. Hereditary nonpolyposis colorectal cancer: Lynch syndromes I and II. Gastroenterol Cfin North Am 1988; 17679-712. 2. Mecklin J-P. Frequency of hereditary colorectal carcinoma. Gastroenterology 1987; 93:1021-1025. 3. Mecklin J-P, Jarvinen HJ. Tumor spectrum in cancer family syndrome. Cancer (submitted for publication). 4. Lynch HT, Ens J, Lynch JF, Watson P. Tumor variation in three extended Lynch syndrome I1 kindreds. Am Gastroenteroll988; 83:741-747. 5. Lynch HT, Watson P, Kriegler M et al. Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome 11). Dis Colon Rectum 1988; 31:372-377. 6. Lynch HT, Voorhees GJ, Lanspa SJ, McGreevy PS, Lynch JF. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: A family study. Br Cancer 1985; 52:271-273. 7. Finnish Cancer Registry. Cancer incidence in Finland 1984. Cancer Statistics of the National Board of Health. Helsinki: 1989. 8. Sugihara K, Muto T, Kamiya J, Konishi F, Sawada T, Morioka Y. Gardner syndrome associated with periampullary carcinoma, duodenal and gastric adenomatosis. Dis Cofon Rectum 1982; 25~766-771. 9. Jarvinen HT, Sipponen P. Gastroduodenal polyps in familial adenomatous and juvenile polyposis. Endoscopy 1986; 18:230234. 10. Jagelman DG, DeGosse JJ, Bussey HJR, The Leeds Castle Polyposis Group. Upper gastrointestinalcancer in familial adenomatous polyposis. Lancet 1988; 1:1149-1151. 11. Jarvinen HJ, Nyberg M, Peltokallio P. Bfiary involvement in familial adenomatosis coli. Dis Colon Rectum 1983; 26:525-528.
The Association Between Cholangiocarcinoma and Hereditary Nonpolyposis Colorectal Carcinoma 1.-P. Mecklin, MD,* H. 1.Jarvinen, MD,t and M. Virolainen, MD$
Eighteen patients with a biliopancreatic carcinoma in 15 different cancer famiIy syndrome (CFS) families were studied. Only families with three or more first-degreerelatives with colorectal carcinoma were included, and other characteristics of CFS were required in at least two cases. In 14 patients, the histologic specimen was available for reevaluation. In 11 (79%), the tumor was confirmed as a carcinoma of the biliary tract or papilla of Vater. In three (21%),carcinoma of the pancreas was the most probable alternative. In all- four patients without histologic reevaluation, the diagnosis had been carcinoma of the biliary tract. This study suggests that carcinoma of the biliary tract or papilla of Vater k associated more commonly with CFS than with carcinoma of the pancreas. In this respect, CFS resembles familial adenomatosis coli, in which this association previously has been established. Cancer 1992; 691112-1114.
Hereditary nonpolyposis colorectal cancer (HNPCC), also known as cancer family syndrome (CFS), seems to be the most common verifiable risk factor of colorectal carcinoma and includes 4% to 6% of all colorectal carcinoma cases.lZ2 The most common extracolonic tumors associating with CFS are endometrial and gastric carcinomas.'~~ Carcinoma of the pancreas also has been observed in families with CFS,4,5and one family with HNPCC and three family members affected by pancreatic carcinoma recently was reported.6However, details of histologic documentation have not been included in these publications. We analyzed the 18 biliopancreatic carcinomas found in 40 verified CFS families in the Finnish CFS registry in an attempt to find the exact origin
From the *Department of Surgery, Jyvaskyla Central Hospital, Jyvaskyla, the tSecond Department of Surgery, Helsinki University Central Hospital, Helsinki, and the $Department of Pathology, Helsinki University, Finland. Supported by the Finnish Cancer Foundation and the Finnish Foundation for Gastroenterology, Helsinki. Address for reprints: J.-P. Mecklin, MD, Jyvaskyla Central Hospital, 40620 Jyvaskyla, Finland. Accepted for publication November 15, 1991.
of the tumors and to evaluate possible associations with the hereditary trait. Patients and Methods
Families with HNPCC have been studied systematically by the Finnish CFS registry since 1983. Within 6 years, almost 100 different cancer families have been filed at the registry. Forty fully examined families were definite CFS families when the minimum criterion was at least three first-degree relatives with colorectal carcinoma with at least two such members expressing one of the following features typical of CFS: (1)a first diagnosis at age younger than 50 years, (2) multiple primary colorectal carcinomas (synchronous or metachronous), and (3) the occurrence of additional primary carcinomas. The total number of affected family members in these 40 families was 315 (174 men and 141 women; mean age, 47.9 years), with a total of 472 separate tumors or diffuse malignant lesions. Details of these families and the overall tumor spectrum (Table 1)have been published el~ewhere.~ Eighteen patients (5.7%) had a primary biliopancreatic carcinoma, which was the third most common extracolonic malignancy next to endometrial and gastric cancer. The clinical data and histologic specimens, when available, of these 18 patients were obtained for reevaluation. Complete hospital records and histologic specimens were available in 14 patients. In two patients, hospital records and the original pathologic report were obtainable, but in two, the death certificate was the only document available. Results
The mean age of the 18 patients studied (10 men and 8 women) at the time biliopancreatic carcinoma was diagnosed was 55.7 years (range, 29 to 80 years). The mean age was 54 years in those nine patients in whom biliopancreatic carcinoma was the only malignant lesion observed; it was 65 years in patients with multiple
Cholangiocarcinoma and Colorectal CA/Mecklin et al. Table 1. Tumor Distribution of 315 Patients in 40 Families With Hereditary Nonpolyposis Colorectal Cancer Tumor No.(%) Colorectum Uterus Stomach Biliopancreatic Urinary tract Breast Sarcomas Skin Small bowel Lung Ovary Other NUD Total NUD: Tumor location not specified. * l'ercentaee urouortion in all uatientshn women.
tumors. Multiple (two to eight) metachronous cancers had been diagnosed in nine (50%) patients, with one or multiple colorectal carcinomas in eight of them (Table 2). The histologic specimen was reevaluated in 14 patients (Table 2, Patients l to 14). In l l (79%) of these (Patients 1 to ll), the tumor was an extrapancreatic adenocarcinoma, originating from the biliary tract in 7 (intrahepatic, one; extrahepatic, six) and from the pa-
1113
pilla of Vater in 4. Carcinoma of the pancreas was the most likely site of the tumor in three patients (12 to 14). In four patients, the histologic specimen were not available for reevaluation (Table 2, Patients 15 to 18).In two patients, the diagnosis of intrahepatic cholangiocarcinoma was based on biopsy and relevant radiologic examinations excluding the possibility of metastases. In one of these, the patient underwent surgery, and the pancreas also was examined during the operation. In two patients, the death certificate was the only available data (Table 2, Patients 15 to 16), and therefore it was impossible to c o n b the diagnosis retrospectively. The overall prognosis was poor. The tumor was resected with curative intent in one patient only, and none of the patients survived longer than 2 years after the diagnosis of biliopancreatic carcinoma was made, In seven patients, the stomach and duodenum had been examined properly to exclude gastric and duodenal polyps. In four, this was confirmed during the autopsy; in one, by gastroscopy; and in one, by a barium meal. For the seventh patient, a pancreaticoduodenectomy was done for ampullary carcinoma. No polyps were observed in the surgical specimen. Discussion
In our study, several findings indicate indirectly that carcinoma of the biliary tract is associated with the HNPCC syndrome. One half of the patients were indis-
Table 2. Sex, Age, Year of Diagnosis, Location of Biliopancreatic Carcinomas, and Distribution of Metachronous Tumors of Studv Subiects Patient no.
Sex/age (yr)
Year
Basis of diagnosis
Location
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
M/64 M/38 F/40 F/54 M/56 F/67 F/72 F/58 M/63 F/67 M/77 M/52 M/58 M/74 F/80 M/54 M/29 F/72
1982 1957 1984 1983 1986 1985 1985 1981 1983 1982 1987 1983 1986 1988 1957 1951 1959 1972
Biopsy Operation Operation Operation Operation Operation Operation Operation Operation Operation Operation Autopsy Autopsy Autopsy Death certificate Death certificate Operation Biopsy
Intrahepatic Common bile duct Common bile duct Common bile duct Common bile duct Common bile duct Common bile duct Ampulla of Vater Ampulla of Vater Ampulla of Vater Ampulla of Vater Pancreas Pancreas Pancreas Common bile duct Intrahepatic Intrahepatic Intrahepatic
Colon 36, ovary 45, uterus 46, stomach 50, colon and rectum 57, skin 59, suprarenal adenoma 65. t Colon 57, colon X 2 60, colon X 2 64, rectum 73, skin 75.
Metachronous tumors
Colon Uterus, colon
Colon 8 different* 7 differentt Colon X 2, sarcoma Colon X 2, rectum Colon X 2, stomach
Uterus
1114
CANCER March 2,1992, Volume 69, No. 5
putably ones with HNPCC and multiple malignant lesions. Biliopancreatic carcinoma was the fourth most common tumor in the families with HNPCC after colorectal, endometrial, and gastric carcinoma. Most of the tumors were biliary tract or ampullary carcinomas. In only three instances (17%)was the pancreas the most probable origin of the tumor, and no case of carcinoma of the gall bladder was observed. In the general Finnish population, biliopancreaticcarcinoma is the ninth most common malignant lesion, and most of these tumors in both sexes originate in the pancreas. The proportion of extrapancreatic carcinomas is only 40% in women and 20% in men.' An association between pancreatic carcinoma and HNPCC has been suggested in single-family report^.^,^ In addition, carcinoma of the biliary tract and duodenum has been observed in two members of a well-documented family with HNPCC reported previously,4 but the histologic details of biliopancreatictumors were usually missing in family reports of HNPCC kindreds. Interestingly, biliary and ampullary tumors are common in patients with familial adenomatous polyposis of the colon (FAP),*-" which can be seen as a counterpart to HNPCC from a genetic point of view. However, pancreatic carcinoma has not been reported, more frequently in FAP than in the general population.8 Our observations of 40 families with HNPCC and 14 biliary tract or ampullary carcinomas suggest the presence of a similar tumor spectrum in HNPCC and FAP." In FAP, however, there is much evidence that carcinomas of the upper gastrointestinal tract arise from preexisting duodenal or juxtapapillary adenomas?" although no such premalignant lesions were detected in our patients, even though seven of them were examined in this respect. Nonetheless, the topographic analogy in upper gastrointestinal tumors between HNPCC and FAP may reflect a similar or closely related pathogenic mechanism, e.g., a metabolic alteration in bile acid synthesis. The altered metabolites may act as tumorpromoting factors, possibly through the adenoma-carcinoma seq~ence.~~" Our results indicate the need for a more accurate diagnostic workup for extracolonic carcinomas in patients with HNPCC to clarify the real tumor spectrum of this syndrome. A preoperative gastroscopy and abdominal ultrasound sonography is recommended for such patients while waiting for surgery on colonic or other abdominal carcinomas. If abnormal findings are observed in the biliary tract preoperatively or peropera-
tively, needle cholangiography should be done. Six of our patients had been operated on within a few years before the carcinoma of the biliary tract was diagnosed. Therefore, a systematic and careful exploration of the biliary tract may detect an asymptomatic biliary tract tumor as has been observed in patients with FAP." In conclusion, tumors of the biliary tract and ampulla of Vater seem to belong to the tumor spectrum of HNPCC rather than to that of pancreatic carcinoma. Colorectal and endometrial cancers are by far the most common tumors of this hereditary syndrome and justify screening of asymptomatic family members. However, the association of bile duct tumors with HNPCC becomes important in the treatment and follow-up of affected patients. It is suggested that upper gastrointestinal tract endoscopy, abdominal ultrasound sonography, and liver function tests should be a part of the diagnostic workup and follow-up program of patients with HNPCC and colorectal or endometrial tumors. References 1. Lynch HT, Lanspa SJ, Boman BM et al. Hereditary nonpolyposis colorectal cancer: Lynch syndromes I and II. Gastroenterol Cfin North Am 1988; 17679-712. 2. Mecklin J-P. Frequency of hereditary colorectal carcinoma. Gastroenterology 1987; 93:1021-1025. 3. Mecklin J-P, Jarvinen HJ. Tumor spectrum in cancer family syndrome. Cancer (submitted for publication). 4. Lynch HT, Ens J, Lynch JF, Watson P. Tumor variation in three extended Lynch syndrome I1 kindreds. Am Gastroenteroll988; 83:741-747. 5. Lynch HT, Watson P, Kriegler M et al. Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome 11). Dis Colon Rectum 1988; 31:372-377. 6. Lynch HT, Voorhees GJ, Lanspa SJ, McGreevy PS, Lynch JF. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: A family study. Br Cancer 1985; 52:271-273. 7. Finnish Cancer Registry. Cancer incidence in Finland 1984. Cancer Statistics of the National Board of Health. Helsinki: 1989. 8. Sugihara K, Muto T, Kamiya J, Konishi F, Sawada T, Morioka Y. Gardner syndrome associated with periampullary carcinoma, duodenal and gastric adenomatosis. Dis Cofon Rectum 1982; 25~766-771. 9. Jarvinen HT, Sipponen P. Gastroduodenal polyps in familial adenomatous and juvenile polyposis. Endoscopy 1986; 18:230234. 10. Jagelman DG, DeGosse JJ, Bussey HJR, The Leeds Castle Polyposis Group. Upper gastrointestinalcancer in familial adenomatous polyposis. Lancet 1988; 1:1149-1151. 11. Jarvinen HJ, Nyberg M, Peltokallio P. Bfiary involvement in familial adenomatosis coli. Dis Colon Rectum 1983; 26:525-528.
