—  SHORT COURSE  —

Disorders of the Intra- and Extrahepatic Bile Ducts

Case 11 - Biliary Cystadenocarcinoma Arising in Benign Cystadenoma

Kay Washington, M.D., Ph.D.
Pathology, C-3321 MCN
Vanderbilt University Medical Center
Nashville, TN 37232-2561


Clinical History
This 62 year old woman presented to the emergency room with crushing chest pain, diagnosed as angina, and was found to have an enlarged liver. Abdominal CT scan showed two cystic masses in the liver and bilateral adrenal hyperplasia but no adenopathy. Positron emission scan showed two metabolically active areas within one of the cystic masses. At surgery a small amount of mucoid ascites was found. The cystic hepatic lesions were resected; this section is from the larger mass, which measured 8.6 cm in greatest dimension.

Morphologic Findings
In the more cystic areas, the tumor is composed of cysts of varying sizes, lined by a single layer of cuboidal to columnar epithelium with apical mucin. Occasional goblet cells are identified. The stroma is cellular and resembles ovarian stroma, with focal hyalinization and inflammation. In the more solid portion, the tumor forms complex papillary structures lined by multiple layers of large atypical cells. Loss of nuclear polarity is seen in these areas, and there are numerous mitoses, some atypical. The cells have large pleomorphic nuclei and a high nuclear to cytoplasmic ratio. Focally frank invasion of the stroma by small clusters of atypical cells and single cells is identified. Borderline areas with nuclear crowding and intermediate cellular atypia and without papillary formations are also present.

Click on each slide thumbnail image for an enlarged view:

Slide 25
Adenocarcinoma Arising in Biliary Cystadenoma
Cytologically malignant cells forming cribriform and papillary structures infiltrate the cyst wall.
Slide 26
Biliary Cystadenoma with Mesenchymal Stroma
The cysts of biliary cystadenoma are lined by simple columnar to cuboidal epithelium; goblet cells are occasionally seen. The underlying mesenchymal stroma may be densely packed and resemble ovarian stroma, a feature found exclusively in female patients.

Diagnosis: Biliary Cystadenocarcinoma Arising in Benign Cystadenoma

The benign biliary epithelial tumors are the bile duct adenoma and the biliary cystadenoma. Bile duct adenomas are generally incidental findings at surgery or autopsy. They appear as discrete firm white masses usually 1 centimeter or less in diameter and are often subcapsular. Microscopically they are composed of a compact uniform proliferation of ductular structures in a desmoplastic stroma. The lack of cytologic atypia and lack of infiltration are features serving to distinguish the biliary adenoma from cholangiocarcinoma or metastatic carcinoma. Distinction from a biliary microhamartoma or von Meyenburg complex is occasionally difficult, but the biliary microhamartoma is made up of dilated bile duct-like structures, occasionally containing bile, located adjacent to a portal tract.

The biliary cystadenoma is an uncommon hepatic neoplasm occurring predominantly in women. These lesions are large multiloculated cysts histologically similar to mucinous cystic tumors arising in the pancreas. The cysts are lined by mucin-secreting cells similar to bile duct epithelium ranging from flattened cuboidal to tall columnar; occasional goblet cells are seen. The epithelial lining is usually simple, although areas of nuclear pseudostratification and crowding may be seen. In tumors from men, the supporting stroma is composed of dense fibrous tissue; in women, the stroma may be densely cellular and resemble ovarian stroma. The biliary cystadenoma should be distinguished from the simple biliary cyst, which is unilocular and lacks a distinctive supporting stroma.

Biliary cystadenocarcinoma is a rare tumor, generally arising in a pre-existing biliary cystadenoma. These tumors arise in adults, and although benign biliary cystadenomas are more common in women, for cystadenocarcinomas the sex ratio is approximately 1:1 .46  The most common presenting symptoms are abdominal pain or an abdominal mass. The etiology remains unknown, although there are reports of cystadenocarcinomas arising in the setting of polycystic liver disease, such as Caroli's disease .47 

Gross Morphology
Most biliary cystadenocarcinomas are multilocular, although rare unilocular cases have been reported .47  Cystadenocarcinomas in one series ranged in size from 3 to 30 cm, essentially no different in size from benign biliary cystadenomas .46  The cyst fluid may be clear mucinous, bile-stained, or blood tinged. The cyst lining may contain papillary projections into the cyst lumen. Areas of solid thickening and large papillary projections are clues to malignancy.

Microscopic Features
The epithelial lining of the cysts generally consists of tall columnar cells and should display cytologic features of malignancy. The tumor infiltrates the underlying cyst wall. Most biliary cystadenocarcinomas are well-differentiated; the most common patterns are a tubulopapillary or tubular adenocarcinoma. Rarely, the tumor shows adenosquamous differentiation. The stroma is variable in biliary cystadenocarcinomas; ovarian-type stroma is often present in tumors in women; in men, the stroma consists of dense fibrosis.

Determination of Malignancy
The prediction of behavior from morphologic features is difficult in cystic mucinous neoplasms. Many otherwise benign biliary cystadenomas have areas of nuclear enlargement, crowding, and stratification, considered areas of dysplastic change. Many pathologists reserve the term "cystadenocarcinoma" for cases with frankly invasive adenocarcinoma involving the stroma or adjacent parenchyma. Surgical resection offers the greatest opportunity for cure; long-term survival is relatively high for women with biliary cystadenocarcinomas arising in pre-existing cystadenomas with ovarian-type stroma. Cystadenocarcinomas in men may have a more aggressive course .46 

References

  1. Colombari R, Tsui WM: Biliary tumors of the liver. [Review] [108 refs]. Seminars in Liver Disease 15:402-13, 1995.
  2. Nakeeb A, Pitt HA, Sohn TA, et al: Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Annals of Surgery 224:463-73, 1996.
  3. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 31:7-11, 2000.
  4. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo Clin Proc 68:874-9, 1993.
  5. Holzinger F, Z'graggen K, Buchler MW. Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma. Ann Oncology 10 Suppl 4:S122-26, 1999.
  6. Koo SH, Ihm CH, Kwon KC, Park JW, et al. Genetic alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Genetics & Cytogenetics 130:22-8, 2001.
  7. Boberg KM, Schrumpf E, Bergquist A, Broome U, et al. Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development. J Hepatol 32:374-80, 2000.
  8. Kubicka S, Kuhnel F, Flemming P, Hain B, et al. K-ras mutations in the bile of patients with primary sclerosing cholangitis. Gut 48:403-8, 2001.
  9. Lee S, Kim WH, Jung HY, et al. Aberrant CpG island methylation of multiple genes in intrahepatic cholangiocarcinoma. Am J Pathol 161:1015-22, 2002.
  10. Patel AH, Harnois DM, Klee GG, LaRusso NF , Gores, GJ. The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 95: 204-7, 2000.
  11. van Leewen DJ, Reeders JWAJ. Primary sclerosing cholangitis and cholangiocarcinoma as a diagnostic and therapeutic dilemma. Ann Oncol 10 Suppl 4:122-6, 1999.
  12. Hultcrantz R, Olsson R, Daneilsson A, et al. A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatology 30:669-73, 1999.
  13. Su CH, Tsay SH, Wu CC, et al: Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Annals of Surgery 223:384-94, 1996.
  14. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Annals of Surgery 234(4):507-19, 2001.
  15. Klempnauer J, Ridder GJ, von Wasielewski R, et al: Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. Journal of Clinical Oncology 15:947-54, 1997.
  16. Klempnauer J, Ridder GJ, Werner M, et al: What constitutes long term survival after surgery for hilar cholangiocarcinoma? Cancer 79:26-34, 1997.
  17. Nagorney DM, Donohue JH, Farnell MB , et al: Outcomes after curative resections of cholangiocarcinoma. Archives of Surgery 128:871-879, 1993.
  18. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Trransplantation 690:1633-7, 2000.
  19. Greene FL , Page DL, Fleming ID, et al: AJCC Cancer Staging Manua l, 6 th ed . New York : Springer-Verlag, 200 2.
  20. Layfield LJ, Wax TD, Lee JG, Cotton PB. Accuracy and morphologic aspects of pancreatic and biliary duct brushings. Acta Cytologica 39:11-18, 1995.
  21. Bardales RH, Stanley MW, Simpson DD, Baker SJ, et al. Diagnostic value of brush cytology in diagnosis of duodenal, biliary, and ampullary neoplasms. Am J Clin Pathol 109:540-8, 1998.
  22. Vadmal MS, Byrne-Semmelmeier S, Smilari TF, Hajdu IS. Biliary tract brush cytology. Acta Cytologica 44:533-8, 2000.
  23. Trent V, Khurana KK, Pisharodi LR. Diagnostic accuracy and clinical utility of endoscopic bile duct brushings in the evaluation of biliary strictures. Arch Pathol Lab Med 123:712-5, 1999.
  24. Kurzawinski TR, Deery A, Dooley JS, Dick R, Hobbs KEF, Davidson BR. A prospective study of biliary cytology in 100 patients with bile duct strictures. Hepatology 18:1399-1403, 1993.
  25. Glasbrenner B, Ardan M, Boeck W, Preclik, et al. Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy 31:712-7, 1999.
  26. Tascilar M, Sturm PDJ, Caspers E, Smit M, et al. Diagnostic p53 immunostaining of endobiliary brush cytology: preoperative cytology compared with the surgical specimen. Cancer Cytopathology 87:306-11, 1999.
  27. Yamanaka N, Okamoto E, Ando T, et al: Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma. Cancer 76:2449-56, 1995.
  28. Rubel LR, Ishak KG: Thorotrast-associated cholangiocarcinoma. An epidemiologic and clinicopathologic study. Cancer 50:1408-15, 1982.
  29. Terada T, Kida T, Nakanuma Y, et al: Intrahepatic cholangiocarcinomas associated with nonbiliary cirrhosis. A clinicopathologic study. Journal of Clinical Gastroenterology 18:335-42, 1994.
  30. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10, 2002.
  31. Chou FF, Sheen-Chen SM, Chen CL, et al: Prognostic factors of resectable intrahepatic cholangiocarcinoma. Journal of Surgical Oncology 59:40-4, 1995.
  32. Kawarada Y, Yamagiwa K, Das BC . Analysis of the relationships between clinicopathologic factors and sur v i v al time in intrahepatic cholangiocarcinoma.
  33. Nakajima T, Tajima Y, Sugano I, et al: Intrahepatic Cholangiocarcinoma with sarcomatous change. Cancer 72:1872-7, 1993.
  34. Rullier A, Le Bail B, Fawaz, R, et al. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol 24:870-6, 2000.
  35. Sasaki A, Kawano K, Aramaki M, et al. Immunohistochemical expression of cytokeratins in intrahepatic cholangiocarcinoma and metastatic adenocarcinoma of the liver. J Surg Oncol 70:103-8, 1999.
  36. Ferrell L: Malignant liver tumors that mimic benign lesions: analysis of five distinct lesions. [Review] [37 refs]. Seminars in Diagnostic Pathology 12:64-76, 1995.
  37. Tot T. Adenocarcinomas metastatic to the liver: the value of cytokeratins 20 and 7 in the search for unknown primary tumors. Cancer 85:171-7, 1999.
  38. Riopel MA, Klimstra DS, Godellas CV, Blumgart LH, Westra WH. Intrabiliary growth of metastatic colonic adenocarcinoma: a pattern of intrahepatic spread easily confused with primary neoplasia of the biliary tract. Am J Surg Pathol 21:1030-6, 1997.
  39. Okano K, Yamamoto J, Moriya Y, Akasu T, et al. Macroscopic intrabiliary growth of liver metastases from colorectal cancer. Surgery 126:829-34, 1999.
  40. Ikeda Y, Matsuma T, Adachi E, Hayashi H, et al. Hepatocellular carcinoma of the intrabiliary growth type. Int Surg 82:76-8, 1997.
  41. Lai ST, Lam KT, Lee KC. Biliary tract invasion and obstruction by hepatocellular carcinoma: report of five cases. Postgrad Med J 68:961-3, 1992.
  42. Morcos M, Dubois S, Bralet MP, et al. Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum. Am J Clin Pathol 116:738-43, 2001.
  43. Goodman ZD, Ishak KG, Langloss JM: Combined hepatocellular-cholangiocarcinoma: a histologic and immunohistochemical study. Cancer 55:124-135, 1984.
  44. Tickoo SK , Zee SY, Obiekwe S, et al. Combined hepatocellular-cholangiocarcinoma: a histopathologic, immunohistochemical, and in situ hybridization study. Am J Surg Pathol 26:989-97, 2002.
  45. Maeda T, Adachi E, Kajiyama K, et al: Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Human Pathology 26:956-64, 1995.
  46. Devaney K, Goodman ZD, Ishak KG: Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients. American Journal of Surgical Pathology 18:1078-91, 1994.
  47. Theise ND , Miller F, Worman HJ, et al: Biliary cystadenoma arising in a liver with fibropolycystic disease. Archives of Pathology and Laboratory Medicine 117:163-5, 1993.