- Email: [email protected]
Association between pancreatic cystadenocarcinoma, malignant liver cysts, and polycystic disease of the kidney
GASTROENTEROLOGY 1997;112:2104–2107
Association Between Pancreatic Cystadenocarcinoma, Malignant Liver Cysts, and Polycystic Disease of the Kidney YARON NIV,* CHANA TURANI,‡ ERNESTO KAHAN,§ and GERALD M. FRASER* Departments of *Gastroenterology and §Family Medicine, Rabin Medical Center, Beilinson Campus, Tel-Aviv University, Sackler School of Medicine, Petach-Tikva; and ‡Department of Pathology, Rebecca Sieff Hospital, Safed, Israel
Polycystic kidney disease is an autosomal dominant disease that may be associated with cystic disease of the liver. In women, the cysts may develop early and be more troublesome than in men. Cystadenocarcinoma of the pancreas is uncommon, comprising 1% of primary pancreatic malignancies. This case report is the first to describe a familial association between polycystic kidney disease and cystadenocarcinoma of the pancreas and liver in the English medical literature. A patient with autosomal dominant polycystic kidney disease (ADPKD) and multiple hepatic cysts developed cystadenocarcinoma of the pancreas with multiple malignant liver cysts. The patient’s mother, sister, and niece had ADPKD, and the patient’s sister also died of pancreatic cystadenocarcinoma. We believe that the development of these two disease entities in which the primary pathology is cyst formation has a genetic association.
P
olycystic liver disease is observed in association with autosomal dominant polycystic kidney disease (ADPKD).1 – 5 The gene for ADPKD-1 is the most common, accounting for 85% of cases, and is located on chromosome 16p between the flanking markers D16S84 and D16S125. This region is 750 kilobases long and has been cloned.6 The gene for ADPKD-2 has been assigned to chromosome 4, and the location of the gene for ADPKD-3 in unknown. Hepatic cysts usually develop later than the renal cysts and cause minimal symptoms. However, in women, the cystic disease of the liver may develop earlier and become symptomatic.3 – 5 The liver cysts are believed to be the result of dilatation of biliary hamartomas similar to the process that causes cysts in the kidney. Cystadenocarcinoma of the pancreas is an uncommon tumor that accounts for only 1% of primary pancreatic malignancies.7 – 12 It arises by malignant transformation of a cystadenoma, and 82% occur in women with an average age of 55 years.7 Pancreatic cysts occur in 5%– 10% of patients with ADPKD, although a familial association between cystadenocarcinoma of the pancreas and / 5e1d$$0034
05-12-97 08:04:43
gasa
ADPKD has not been described previously in the English medical literature.
Case Report The patient was a 68-year-old unmarried woman who was transferred to our institution because of severe abdominal pain and jaundice. The patient’s past medical history was pertinent for arterial hypertension and ADPKD. In the 6-week period before admission, she complained of epigastric pain and abdominal distention and had lost 6 kg in weight. In the 3week period before admission, her urine darkened and she became jaundiced and started to itch. Physical examination showed a temperature of 37.57C and a firm liver with a 20cm span and palpable 8 cm below the costal margin. There was no splenomegaly, ascites, or other stigmata of chronic liver disease. Admission laboratory studies showed abnormal liver enzyme values: aspartate transaminase of 249 IU/L, alanine transaminase of 232 IU/L, alkaline phosphatase of 613 IU/L (normal, õ115 IU/L), and g-glutamyl transpeptidase of 409 IU/L. Total bilirubin level was 1.2 mg/dL. Serological tests for hepatitis A, B, and C were negative. Carcinoembryonic antigen was 2297 ng/mL, and CA 19.9 was 162.2 ng/mL with a normal a-fetoprotein. Abdominal ultrasonography showed a cystic mass in the pancreatic tail and polycystic disease of the liver and left kidney. Computerized tomographic (CT) scan of the upper portion of the abdomen showed an enlarged liver filled with well-marginated areas that had an absorption density equivalent to water, pathognomonic of cysts (Figure 1). CT-guided cytological aspiration of one of the liver cysts revealed malignant epithelial cells (Figure 2). After a downhill course of 24 days, bilirubin level increased to 54.6 mg/dL, pruritus and abdominal pain increased, and the patient died, with a clinical picture of hepatic coma. At autopsy there was a large mass in the tail of the pancreas that histologically proved to be a cystadenocarcinoma (Figure 3). Multiple cysts were evident on the surface of the liver. Microscopic examination showed numerous cysts, lined by cuboidal epithelium similar to the cells of the biliary tract, with malignant transformation (Figure 4). Abbreviations in this paper: ADPKD, autosomal dominant polycystic kidney disease; CT, computerized tomography. q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
WBS-Gastro
June 1997
CYSTADENOCARCINOMA OF THE PANCREAS 2105
Figure 3. Autopsy results: cystadenocarcinoma of the pancreatic tail (original magnification 331).
Figure 1. CT scan showing liver cysts and pancreatic cystadenocarcinoma attached to the spleen.
Family History Details of the patient’s family could be obtained for only one previous generation (Figure 5). Her mother had ADPKD, had arterial hypertension, and died of a cerebrovascular accident. She had 1 healthy brother and 1 sister who had ADPKD, arterial hypertension, and cerebrovascular accident but died of a cystadenocarcinoma of the pancreas. The sister’s daughter (30 years old) has ADPKD but refused any investigation.
Association Between ADPKD and Pancreatic Cystadenocarcinoma
is 2.5:1000,1 – 5 and that for cystadenocarcinoma of the pancreas (1% of pancreatic malignancies) is 0.00052:1000.13 The very low prevalence of the latter makes an etiological relationship between the two entities highly improbable. If we assume that ADPKD and pancreatic cystadenocarcinoma are independent and there are no genetic factors for the latter in the present family, the risk of the 4 patients with ADPKD having cystadenocarcinoma should be 0.00052:1000, similar to that of the general population. By contrast, if the 30-year-old daughter is designated as negative, then the observed ratio is 2:4. If an interaction is believed to be the cause of cystadenocarcinoma in this group of ADPKD cases, the attributable proportion or etiological fraction (EF) is 98.9% (attributable risk Å 0.495), EF Å
(Incidence Exposed 0 Incidence Nonexposed) . Incidence Exposed
Tumor incidence rates for pancreatic cancer and more specifically for cystadenocarcinoma were obtained from the literature.13 We attempted to estimate the number of cases of cancers expected if this family had had the same risk of cancers as the general population. The reported incidence for ADPKD
The patient developed metastatic cystadenocarcinoma of the pancreas on the background of ADPKD.
Figure 2. Malignant epithelial cells obtained by CT-guided cytological aspiration of one of the liver cysts (original magnification 501).
Figure 4. Autopsy results: cystic liver metastases or possible transformation from cystic epithelium to cancer (arrow) (original magnification 331).
/ 5e1d$$0034
05-12-97 08:04:43
gasa
Discussion
WBS-Gastro
2106 NIV ET AL.
GASTROENTEROLOGY Vol. 112, No. 6
Figure 5. Pedigree of a kindred with ADPDK and pancreatic cystadenocarcinoma. Circles denote female family members, squares male family members, and symbols with a slash deceased family members. The proband is indicated by the arrow. Current age (in years) or age at death is given below each figure.
Cystadenoarcinoma of the pancreas is uncommon and compromises only 1% of pancreatic malignancies.7,14 In our patient’s family, 2 cases of this tumor occurred in sisters from a family in which there were 4 cases of ADPKD over three generations. We found only one cross-reference between pancreatic neoplasms and ADPKD in the MEDLINE search (English literature).15 This reference is a case report of ductular (noncystic) pancreatic adenocarcinoma. ReMine et al. collected 500 cases of pancreatic cystic neoplasms from the English literature.16 No association with ADPKD was found, and it appears that this association has not been previously reported. There are several lines of evidence that the liver cysts in ADPKD originate from biliary epithelium and are the result of progressive dilatation of biliary microhamartomas17 – 23: low glucose concentration of the cyst fluid, presence of secretory immunoglobulin A, demonstration of cytokeratin 19, and secretory responsiveness to intravenous administration of secretin. When the liver develops, the distal anlage contains the hepatic cells and the proximal anlage the major bile ducts. The two grow together, but intralobular bile ducts are found in the hepatic anlage and form among the parenchymal cells. Because the liver makes more intrahepatic bile ducts than it needs, many involute with time. Uncommonly, the bile ducts do not involute, and they then form cuboidal lined cysts that do not communicate with the rest of the biliary tree. Biliary microhamartomas may dilate and grow into cysts and become disconnected from the biliary tree. As in other congenital cysts of the liver and biliary tree, malignant transformation may be expected (e.g., in choledochal cyst).24 The association between multiple renal cysts and cystic pancreatic tumors is well known in von Hippel– Lindau disease; this may be a genetic analogue to our case. / 5e1d$$0034
05-12-97 08:04:43
gasa
Because primary cystadenocarcinoma of the pancreas metastasizes to the liver as a solid lesion, the most likely cause of the hepatic and pancreatic tumors in our cases was malignant transformation of lining cells in liver and pancreatic cysts of ADPKD. The morphological documentation supports this hypothesis because we could observe transformation from normal cystic epithelium to cancer (Figure 4). The etiologic significance of pancreatic cystadenocarcinoma in ADPKD kindred remains enigmatic. There are several possible explanations: (1) the simultaneous occurrence in this family may be fortuitous; (2) pancreatic cystadenocarcinoma may be integral to the ADPKD genotype; and (3) pancreatic cystadenocarcinoma may be a pleiotrophic manifestation of ADPKD cancer-prone pancreatic and biliary epithelium genotype that, as a result of sequential environmental exposures, perturbs this genotype. Abnormalities in the renal basement membrane components of patients with ADPKD and in proliferation, development, and polarization of cystic epithelium have been described.25,26 These abnormalities may occur in the liver and pancreas, leading to malignant transformation. We believe that the development of these two disease entities with a primary pathology of cyst formation has a genetic association.
References 1. Iglesias CG, Torres VE, Offord KP, Holley KE. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am J Kidney Dis 1983;2:630–639. 2. Milutinovic J, Fialkow PJ, Rudd TG. Liver cysts in patients with autosomal dominant polycystic kidney disease. Am J Med 1980; 68:741–744. 3. Levine E, Cook LT, Grantham JJ. Liver cysts in autosomal dominant polycystic kidney disease: clinical and computed tomographic study. Am J Radiol 1985;145:229–233. 4. Gabow FA, Johnson AM, Kaehny WD. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 1990;11:1033–1037. 5. Que F, Nagorney DM, Gross JB. Liver resection and cyst fenetration in the treatment of severe polycystic liver disease. Gastroenterology 1995;108:487–494. 6. Grantham JJ. Polycystic kidney disease—there goes the neighborhood. N Engl J Med 1995;333:56–57. 7. Cello JP. Carcinoma of the pancreas. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal diseases. 5th ed. Philadelphia: Saunders, 1993:1682–1694. 8. Hodgkinson DJ, ReMine WH, Weiland LH. Pancreatic cystadenoma—a clinicopathological study of 45 cases. Arch Surg 1978; 113:512. 9. Corrente RF. Cystadenocarcinoma of the pancreas. Am J Surg 1980;139:265–267. 10. Golematis B, Georgakakis A, Bastounis E. Papillary cystadenocarcinoma of the pancreas. Am J Gastroenterol 1977;67:600–603. 11. Warshaw AL, Fernandez-Del Castilo C. Pancreatic carcinoma. N Engl J Med 1992;326:455–465. 12. Compagno J, Oertel JE. Mucinous cyst neoplasm of the pancreas with overt and latent malignancy (cystadenocarcinoma and cyst-
WBS-Gastro
June 1997
13. 14. 15. 16. 17.
18.
19.
20.
21.
CYSTADENOCARCINOMA OF THE PANCREAS 2107
adenoma). A clinicopathological study of 41 cases. Am J Clin Pathol 1978;69:573–580. Cancer Statistics. CA Cancer J Clin 1995;45:8–30. Cubilla AL, Fitzgerald PJ. Classification of pancreatic cancer (nonendocrine). Mayo Clin Proc 1979;54:449–458. Cryer PE, Kissane JM. Obstructive jaundice in a patient with polycystic disease. Am J Med 1977;62:616–626. ReMine SG, Frey CF, Rossi RL, Munson L, Braasch JW. Cystic neoplasm of the pancreas. Arch Surg 1987;122:443–446. Que F, Nagorney DM, Gross JB, Torres VE. Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroenterology 1995;108:487–494. Babow FA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 1990;11:1033–1037. Fisher J, Mekhjin H, Pritchett ELC, Charme LS. Polycystic liver disease: studies on the mechanisms of cyst fluid formation: a case report. Gastroenterology 1974;66:423–428. Patterson M, Gonzalez-Vitale JC, Fagan CJ. Polycystic liver disease: a study of cyst fluid constituents. Hepatology 1982;2: 475–478. Everson GT, Emmett M, Brown WR, Redmond P, Thickman D. Functional similarities of hepatic cystic and biliary epithelium:
/ 5e1d$$0034
05-12-97 08:04:43
gasa
22.
23.
24.
25. 26.
studies of fluid constituents and in vivo secretion in response to secretin. Hepatology 1990;11:557–565. Jefferson DM, Grubman SA, Cox LJ, Torres VE, Toth I, Perrone RD. Immortalized epithelial cell lines: a model for the study of ADPKD-associated liver disease. In: Gabow PA, Grantham JJ, eds. Proceedings of the fifth international workshop on polycystic kidney disease (abstr). Kansas City, Kansas: Kidney Research Foundation, 1992:19–20. Perrone RD, Grubman SA, Rogers LC, Lee DW, Moy E, Murray SL, Torres VE, Jefferson DM. Continuous epithelial cell lines from ADPKD liver cysts exhibit characteristics of intrahepatic biliary epithelium. Am J Physiol 1995;269:G335–G345. Chaudhuri PK, Chaudhuri B, Schuler JJ, Nyhus L. Carcinoma associated with congenital cystic dilatation of bile ducts. Arch Surg 1982;117:1349–1351. Woo D. Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med 1995;333:18–25. Grantham JJ. Polycystic kidney disease: neoplasia in disguise. Am J Kidney Dis 1990;15:110–116.
Received September 4, 1996. Accepted February 6, 1997. Address requests for reprints to: Yaron Niv, M.D., Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, PetachTikva 49100, Israel. Fax: (972) 3-9210313.
WBS-Gastro
Association Between Pancreatic Cystadenocarcinoma, Malignant Liver Cysts, and Polycystic Disease of the Kidney YARON NIV,* CHANA TURANI,‡ ERNESTO KAHAN,§ and GERALD M. FRASER* Departments of *Gastroenterology and §Family Medicine, Rabin Medical Center, Beilinson Campus, Tel-Aviv University, Sackler School of Medicine, Petach-Tikva; and ‡Department of Pathology, Rebecca Sieff Hospital, Safed, Israel
Polycystic kidney disease is an autosomal dominant disease that may be associated with cystic disease of the liver. In women, the cysts may develop early and be more troublesome than in men. Cystadenocarcinoma of the pancreas is uncommon, comprising 1% of primary pancreatic malignancies. This case report is the first to describe a familial association between polycystic kidney disease and cystadenocarcinoma of the pancreas and liver in the English medical literature. A patient with autosomal dominant polycystic kidney disease (ADPKD) and multiple hepatic cysts developed cystadenocarcinoma of the pancreas with multiple malignant liver cysts. The patient’s mother, sister, and niece had ADPKD, and the patient’s sister also died of pancreatic cystadenocarcinoma. We believe that the development of these two disease entities in which the primary pathology is cyst formation has a genetic association.
P
olycystic liver disease is observed in association with autosomal dominant polycystic kidney disease (ADPKD).1 – 5 The gene for ADPKD-1 is the most common, accounting for 85% of cases, and is located on chromosome 16p between the flanking markers D16S84 and D16S125. This region is 750 kilobases long and has been cloned.6 The gene for ADPKD-2 has been assigned to chromosome 4, and the location of the gene for ADPKD-3 in unknown. Hepatic cysts usually develop later than the renal cysts and cause minimal symptoms. However, in women, the cystic disease of the liver may develop earlier and become symptomatic.3 – 5 The liver cysts are believed to be the result of dilatation of biliary hamartomas similar to the process that causes cysts in the kidney. Cystadenocarcinoma of the pancreas is an uncommon tumor that accounts for only 1% of primary pancreatic malignancies.7 – 12 It arises by malignant transformation of a cystadenoma, and 82% occur in women with an average age of 55 years.7 Pancreatic cysts occur in 5%– 10% of patients with ADPKD, although a familial association between cystadenocarcinoma of the pancreas and / 5e1d$$0034
05-12-97 08:04:43
gasa
ADPKD has not been described previously in the English medical literature.
Case Report The patient was a 68-year-old unmarried woman who was transferred to our institution because of severe abdominal pain and jaundice. The patient’s past medical history was pertinent for arterial hypertension and ADPKD. In the 6-week period before admission, she complained of epigastric pain and abdominal distention and had lost 6 kg in weight. In the 3week period before admission, her urine darkened and she became jaundiced and started to itch. Physical examination showed a temperature of 37.57C and a firm liver with a 20cm span and palpable 8 cm below the costal margin. There was no splenomegaly, ascites, or other stigmata of chronic liver disease. Admission laboratory studies showed abnormal liver enzyme values: aspartate transaminase of 249 IU/L, alanine transaminase of 232 IU/L, alkaline phosphatase of 613 IU/L (normal, õ115 IU/L), and g-glutamyl transpeptidase of 409 IU/L. Total bilirubin level was 1.2 mg/dL. Serological tests for hepatitis A, B, and C were negative. Carcinoembryonic antigen was 2297 ng/mL, and CA 19.9 was 162.2 ng/mL with a normal a-fetoprotein. Abdominal ultrasonography showed a cystic mass in the pancreatic tail and polycystic disease of the liver and left kidney. Computerized tomographic (CT) scan of the upper portion of the abdomen showed an enlarged liver filled with well-marginated areas that had an absorption density equivalent to water, pathognomonic of cysts (Figure 1). CT-guided cytological aspiration of one of the liver cysts revealed malignant epithelial cells (Figure 2). After a downhill course of 24 days, bilirubin level increased to 54.6 mg/dL, pruritus and abdominal pain increased, and the patient died, with a clinical picture of hepatic coma. At autopsy there was a large mass in the tail of the pancreas that histologically proved to be a cystadenocarcinoma (Figure 3). Multiple cysts were evident on the surface of the liver. Microscopic examination showed numerous cysts, lined by cuboidal epithelium similar to the cells of the biliary tract, with malignant transformation (Figure 4). Abbreviations in this paper: ADPKD, autosomal dominant polycystic kidney disease; CT, computerized tomography. q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
WBS-Gastro
June 1997
CYSTADENOCARCINOMA OF THE PANCREAS 2105
Figure 3. Autopsy results: cystadenocarcinoma of the pancreatic tail (original magnification 331).
Figure 1. CT scan showing liver cysts and pancreatic cystadenocarcinoma attached to the spleen.
Family History Details of the patient’s family could be obtained for only one previous generation (Figure 5). Her mother had ADPKD, had arterial hypertension, and died of a cerebrovascular accident. She had 1 healthy brother and 1 sister who had ADPKD, arterial hypertension, and cerebrovascular accident but died of a cystadenocarcinoma of the pancreas. The sister’s daughter (30 years old) has ADPKD but refused any investigation.
Association Between ADPKD and Pancreatic Cystadenocarcinoma
is 2.5:1000,1 – 5 and that for cystadenocarcinoma of the pancreas (1% of pancreatic malignancies) is 0.00052:1000.13 The very low prevalence of the latter makes an etiological relationship between the two entities highly improbable. If we assume that ADPKD and pancreatic cystadenocarcinoma are independent and there are no genetic factors for the latter in the present family, the risk of the 4 patients with ADPKD having cystadenocarcinoma should be 0.00052:1000, similar to that of the general population. By contrast, if the 30-year-old daughter is designated as negative, then the observed ratio is 2:4. If an interaction is believed to be the cause of cystadenocarcinoma in this group of ADPKD cases, the attributable proportion or etiological fraction (EF) is 98.9% (attributable risk Å 0.495), EF Å
(Incidence Exposed 0 Incidence Nonexposed) . Incidence Exposed
Tumor incidence rates for pancreatic cancer and more specifically for cystadenocarcinoma were obtained from the literature.13 We attempted to estimate the number of cases of cancers expected if this family had had the same risk of cancers as the general population. The reported incidence for ADPKD
The patient developed metastatic cystadenocarcinoma of the pancreas on the background of ADPKD.
Figure 2. Malignant epithelial cells obtained by CT-guided cytological aspiration of one of the liver cysts (original magnification 501).
Figure 4. Autopsy results: cystic liver metastases or possible transformation from cystic epithelium to cancer (arrow) (original magnification 331).
/ 5e1d$$0034
05-12-97 08:04:43
gasa
Discussion
WBS-Gastro
2106 NIV ET AL.
GASTROENTEROLOGY Vol. 112, No. 6
Figure 5. Pedigree of a kindred with ADPDK and pancreatic cystadenocarcinoma. Circles denote female family members, squares male family members, and symbols with a slash deceased family members. The proband is indicated by the arrow. Current age (in years) or age at death is given below each figure.
Cystadenoarcinoma of the pancreas is uncommon and compromises only 1% of pancreatic malignancies.7,14 In our patient’s family, 2 cases of this tumor occurred in sisters from a family in which there were 4 cases of ADPKD over three generations. We found only one cross-reference between pancreatic neoplasms and ADPKD in the MEDLINE search (English literature).15 This reference is a case report of ductular (noncystic) pancreatic adenocarcinoma. ReMine et al. collected 500 cases of pancreatic cystic neoplasms from the English literature.16 No association with ADPKD was found, and it appears that this association has not been previously reported. There are several lines of evidence that the liver cysts in ADPKD originate from biliary epithelium and are the result of progressive dilatation of biliary microhamartomas17 – 23: low glucose concentration of the cyst fluid, presence of secretory immunoglobulin A, demonstration of cytokeratin 19, and secretory responsiveness to intravenous administration of secretin. When the liver develops, the distal anlage contains the hepatic cells and the proximal anlage the major bile ducts. The two grow together, but intralobular bile ducts are found in the hepatic anlage and form among the parenchymal cells. Because the liver makes more intrahepatic bile ducts than it needs, many involute with time. Uncommonly, the bile ducts do not involute, and they then form cuboidal lined cysts that do not communicate with the rest of the biliary tree. Biliary microhamartomas may dilate and grow into cysts and become disconnected from the biliary tree. As in other congenital cysts of the liver and biliary tree, malignant transformation may be expected (e.g., in choledochal cyst).24 The association between multiple renal cysts and cystic pancreatic tumors is well known in von Hippel– Lindau disease; this may be a genetic analogue to our case. / 5e1d$$0034
05-12-97 08:04:43
gasa
Because primary cystadenocarcinoma of the pancreas metastasizes to the liver as a solid lesion, the most likely cause of the hepatic and pancreatic tumors in our cases was malignant transformation of lining cells in liver and pancreatic cysts of ADPKD. The morphological documentation supports this hypothesis because we could observe transformation from normal cystic epithelium to cancer (Figure 4). The etiologic significance of pancreatic cystadenocarcinoma in ADPKD kindred remains enigmatic. There are several possible explanations: (1) the simultaneous occurrence in this family may be fortuitous; (2) pancreatic cystadenocarcinoma may be integral to the ADPKD genotype; and (3) pancreatic cystadenocarcinoma may be a pleiotrophic manifestation of ADPKD cancer-prone pancreatic and biliary epithelium genotype that, as a result of sequential environmental exposures, perturbs this genotype. Abnormalities in the renal basement membrane components of patients with ADPKD and in proliferation, development, and polarization of cystic epithelium have been described.25,26 These abnormalities may occur in the liver and pancreas, leading to malignant transformation. We believe that the development of these two disease entities with a primary pathology of cyst formation has a genetic association.
References 1. Iglesias CG, Torres VE, Offord KP, Holley KE. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am J Kidney Dis 1983;2:630–639. 2. Milutinovic J, Fialkow PJ, Rudd TG. Liver cysts in patients with autosomal dominant polycystic kidney disease. Am J Med 1980; 68:741–744. 3. Levine E, Cook LT, Grantham JJ. Liver cysts in autosomal dominant polycystic kidney disease: clinical and computed tomographic study. Am J Radiol 1985;145:229–233. 4. Gabow FA, Johnson AM, Kaehny WD. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 1990;11:1033–1037. 5. Que F, Nagorney DM, Gross JB. Liver resection and cyst fenetration in the treatment of severe polycystic liver disease. Gastroenterology 1995;108:487–494. 6. Grantham JJ. Polycystic kidney disease—there goes the neighborhood. N Engl J Med 1995;333:56–57. 7. Cello JP. Carcinoma of the pancreas. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal diseases. 5th ed. Philadelphia: Saunders, 1993:1682–1694. 8. Hodgkinson DJ, ReMine WH, Weiland LH. Pancreatic cystadenoma—a clinicopathological study of 45 cases. Arch Surg 1978; 113:512. 9. Corrente RF. Cystadenocarcinoma of the pancreas. Am J Surg 1980;139:265–267. 10. Golematis B, Georgakakis A, Bastounis E. Papillary cystadenocarcinoma of the pancreas. Am J Gastroenterol 1977;67:600–603. 11. Warshaw AL, Fernandez-Del Castilo C. Pancreatic carcinoma. N Engl J Med 1992;326:455–465. 12. Compagno J, Oertel JE. Mucinous cyst neoplasm of the pancreas with overt and latent malignancy (cystadenocarcinoma and cyst-
WBS-Gastro
June 1997
13. 14. 15. 16. 17.
18.
19.
20.
21.
CYSTADENOCARCINOMA OF THE PANCREAS 2107
adenoma). A clinicopathological study of 41 cases. Am J Clin Pathol 1978;69:573–580. Cancer Statistics. CA Cancer J Clin 1995;45:8–30. Cubilla AL, Fitzgerald PJ. Classification of pancreatic cancer (nonendocrine). Mayo Clin Proc 1979;54:449–458. Cryer PE, Kissane JM. Obstructive jaundice in a patient with polycystic disease. Am J Med 1977;62:616–626. ReMine SG, Frey CF, Rossi RL, Munson L, Braasch JW. Cystic neoplasm of the pancreas. Arch Surg 1987;122:443–446. Que F, Nagorney DM, Gross JB, Torres VE. Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroenterology 1995;108:487–494. Babow FA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 1990;11:1033–1037. Fisher J, Mekhjin H, Pritchett ELC, Charme LS. Polycystic liver disease: studies on the mechanisms of cyst fluid formation: a case report. Gastroenterology 1974;66:423–428. Patterson M, Gonzalez-Vitale JC, Fagan CJ. Polycystic liver disease: a study of cyst fluid constituents. Hepatology 1982;2: 475–478. Everson GT, Emmett M, Brown WR, Redmond P, Thickman D. Functional similarities of hepatic cystic and biliary epithelium:
/ 5e1d$$0034
05-12-97 08:04:43
gasa
22.
23.
24.
25. 26.
studies of fluid constituents and in vivo secretion in response to secretin. Hepatology 1990;11:557–565. Jefferson DM, Grubman SA, Cox LJ, Torres VE, Toth I, Perrone RD. Immortalized epithelial cell lines: a model for the study of ADPKD-associated liver disease. In: Gabow PA, Grantham JJ, eds. Proceedings of the fifth international workshop on polycystic kidney disease (abstr). Kansas City, Kansas: Kidney Research Foundation, 1992:19–20. Perrone RD, Grubman SA, Rogers LC, Lee DW, Moy E, Murray SL, Torres VE, Jefferson DM. Continuous epithelial cell lines from ADPKD liver cysts exhibit characteristics of intrahepatic biliary epithelium. Am J Physiol 1995;269:G335–G345. Chaudhuri PK, Chaudhuri B, Schuler JJ, Nyhus L. Carcinoma associated with congenital cystic dilatation of bile ducts. Arch Surg 1982;117:1349–1351. Woo D. Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med 1995;333:18–25. Grantham JJ. Polycystic kidney disease: neoplasia in disguise. Am J Kidney Dis 1990;15:110–116.
Received September 4, 1996. Accepted February 6, 1997. Address requests for reprints to: Yaron Niv, M.D., Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, PetachTikva 49100, Israel. Fax: (972) 3-9210313.
WBS-Gastro