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Keywords:

  • papillary carcinoma;
  • extrahepatic bile ducts;
  • p53;
  • MIB-1

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Adenocarcinomas of the extrahepatic bile ducts (EBD) are uncommon neoplasms that are morphologically heterogenous and associated with a poor prognosis. Papillary carcinomas of the EBD, however, appear to follow a much less aggressive clinical course.

METHODS

The authors reviewed the clinical records of nine patients with papillary carcinoma of the EBD, analyzed the microscopic features, and selected immunohistochemical reactivity (p53 and MIB-1) that might correlate with patient survival.

RESULTS

Six patients were male and three were female, with a mean age of 65 years (range, 48–83 years). The clinical presentation of disease in these patients was similar to that reported for conventional adenocarcinoma of EBD. According to their cell phenotypes, these papillary carcinomas were classified as biliary type (7 cases) and intestinal type (2 cases). Most were located in the common bile duct and were well differentiated (7 cases). Five showed minimal expansile invasion into the ductal wall and four were noninvasive. Five patients were treated with a Whipple operation, three underwent segmental resections, and one underwent a left hepatic lobectomy. One patient died of unrelated causes 16 years after a Whipple operation, and another died of postoperative complications. The remaining 7 patients are alive and disease free 1–13 years after surgery.

CONCLUSIONS

Noninvasive and minimally invasive papillary carcinomas of the EBD are associated with excellent long term prognosis regardless of their cytologic features or their immunohistochemical reactivity to p53 and MIB-1. These tumors should be distinguished from biliary papillomatosis, intraductal papillary mucinous carcinomas of the pancreas extending into the bile ducts, papillary adenomas, and papillary hyperplasia. Cancer 2000;89:508–15. © 2000 American Cancer Society.

Representing a small proportion of all malignant epithelial tumors of the extrahepatic bile ducts,1, 2 papillary carcinomas of the extrahepatic bile ducts (EBDs) tend to grow toward the lumen, and only late in their course do they invade the ductal wall and periductal tissues. Because of this feature, they usually follow a protracted clinical course and appear to be associated with a better prognosis than other types of infiltrating adenocarcinoma.3 Due to their rarity, however, a detailed histologic description and knowledge about their natural history based on long term follow-up are lacking. We describe here the clinical and pathologic features of 9 examples of noninvasive, or minimally invasive papillary carcinomas of the extrahepatic bile ducts observed during a 25-year period, and provide evidence that these papillary carcinomas behave as in situ carcinomas.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The files of the Armed Forces Institute of Pathology (AFIP) and the consultation and surgical pathology files of the University of Texas Southwestern Medical Center were searched for papillary carcinomas of the extrahepatic bile ducts. Nineteen cases were found: 13 from the AFIP were accessioned during a 25-year period between 1974 and 1999; the remaining 6 cases from the University of Texas Southwestern Medical Center were collected from 1987 to 1999. Four of these cases were seen in consultation by one of the authors (J.A.-S.). Because only biopsies were obtained in nine patients, invasion into the wall could not be evaluated; therefore, these cases were excluded from the study. Another tumor showing extension beyond the ductal wall was not included in the study. Papillary carcinomas that arose in the ampulla of Vater also were excluded.

Routine hematoxylin and eosin–stained sections were available in all cases. The number of histologic sections examined per case varied from 3 to 11 with an average of 5. From the paraffin blocks available in seven tumors, additional sections were obtained for immunohistochemical stains that were performed on an automated immunostainer (Ventana Bio Tek System, Tucson, AZ) using the standard avidin-biotin peroxidase complex technique and the heat-induced epitope retrieval buffer. Antibodies against p53 (1:50; Dako Co., Carpinteria, CA) and MIB-1 (1:10; Bio Genex, San Ramon, CA) were used. The stains for p53 were scored by using a semiquantitative method to evaluate the intensity of the reaction and the proportion of positive-stained cells.4 Appropriate tissues were used as positive controls. Clinical and follow-up information was obtained from the clinical charts, tumor registries, referring pathologists, or death certificates.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The salient clinical features of the nine patients are presented in Table 1. Six patients were male and 3 were female, ages 48–83 years (mean age, 65 years). None of the patients had ulcerative colitis or primary sclerosing cholangitis, known risk factors for carcinoma of the EBDs. Painless jaundice, abdominal pain, and weight loss were the most common complaints. Only one tumor, the smallest of the series, was an incidental finding during a cholecystectomy for gallstones. Seven tumors were located in the common bile duct, one in the cystic duct, and one in the left hepatic duct. Five patients were treated by a Whipple operation, three had segmental resections, and one underwent a left hepatic lobectomy. One patient died of unrelated causes 16 years after a Whipple operation. Another patient died of postoperative complications. The remaining 7 patients are alive and disease free 12 months to 13 years after surgery. Six of these 7 patients are disease free 5–13 years after surgical therapy.

Table 1. Clinical and Pathologic Features of Nine Patients with Noninvasive and Minimally Invasive Papillary Carcinomas of the Extrahepatic Bile Ducts
Case no.Age (yrs)GenderSymptomLocationTreatmentFollow-up
  1. F: female; CBD: common bile duct; M: male; RUQ: right upper quadrant.

148FChronic cholecystitis, painless jaundice caused by biliary obstructionCBDWhipple operationDied of unrelated causes 16 yrs after surgery
270MPainless jaundice caused by biliary obstructionCBDWhipple operationDisease free 13 yrs
355MRUQ pain, distended and palpable gallbladderCystic ductCholecystectomy and resection of cystic ductDisease free 12 yrs
463MDiscovered during cholecystectomy for gallstonesLeft hepatic ductLeft hepatic lobectomy, resection of left hepatic ductDisease free 12 yrs
583MPainless jaundice caused by biliary obstructionCBDWhipple operationDisease free 6 yrs
658MPainless jaundice caused by biliary obstruction, pruritusCBDSegmental resection of CBDDisease free 8 yrs
778FAbdominal pain and jaundice caused by biliary obstructionCBDWhipple operationDisease free 5 yrs
870FObstructive jaundice, abdominal painCBDWhipple operationDied postoperatively
968MChronic cholecystitis, intermittent jaundice, and biliary obstruction for polypoid mass in CBD; pruritusCBDCholecystectomy and segmental resection of CBDDisease free 12 mos

Macroscopic Features

The tumors appeared as relatively well demarcated exophytic or polypoid masses measuring from 0.9 to 2.3 cm and obstructing the bile ductal lumen. Most had a granular surface. In four tumors, smaller papillary lesions were observed around the main polypoid mass. No invasion into the wall was identified in any of the tumors.

Microscopic Features

Based on cytologic features, seven tumors were classified as biliary type and two as intestinal type. All were characterized by an exophytic proliferation of complex papillary structures with or without gland formation. Seven papillary carcinomas were well differentiated, and two were moderately differentiated (Figs. 1a,b and 2a,b ). Finger-like epithelial processes with fibrovascular cores predominated in all tumors but varied in size from small to large (Figs. 3a,b ). The columnar biliary-type cells lining the papillae were pseudostratified and often had supranuclear cytoplasmic mucin vacoules whereas the columnar intestinal type cells contained little or no mucin (Figs. 4a,b ). Foci of extracellular mucin were noted in two biliary tumors. The cell nuclei were ovoid or fusiform and hyperchromatic or vesicular and contained small or large nucleoli. Mitotic figures were observed in all the tumors but were not numerous. They varied in number from 2 to 5 mitotic figures per 10 high-power fields. Four papillary carcinomas did not invade the fibrotic ductal wall, but two tumors extended into the sacculi of Beale and intramural glands, mimicking invasion (Fig. 5). The remaining five with pushing margins showed superficial stromal infiltration, but none of these infiltrated the full thickness of the bile ductal wall. Four tumors displayed numerous foci of papillary carcinoma separated from the main mass by uninvolved ductal wall and therefore were considered to be multicentric.

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Figure 1. (a) Noninvasive papillary carcinoma of common bile duct. The tumor shows numerous papillary structures that project into the lumen. The fibrotic wall of the common bile duct, however, is intact (H & E, original magnification ×15). (b) Higher magnification of tumor shown in (a). The papillae are lined by columnar cells similar to those of biliary epithelium. The nuclei are ovoid and contain small nucleoli. A few mitotic figures are seen (H & E, original magnification ×200).

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Figure 2. (a) Minimally invasive papillary carcinoma of common bile duct. The pancreas and the thickened fibrotic wall of the common bile duct are seen. The tumor has an exophytic pattern but has invaded the superficial portion of the ductal wall by expansile growth (H & E, original magnification ×10). (b) Higher magnification of tumor is shown in (a). The tumor is moderately differentiated and shows papillary architecture with gland formation and extracellular mucin. Note the pushing margins (H & E, original magnification ×200).

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Figure 3. (a) Long papillary structures lined by pseudostratified columnar biliary-type cells some with supranuclear vacuoles are shown. (b) Short papillary structures lined by columnar biliary-type cells containing supranuclear vacuoles are shown (H & E, original magnification ×200).

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Figure 4. (a) Papillary carcinoma, intestinal type, with minimal invasion of the wall is shown (H & E, original magnification ×50). (b) Higher magnification of papillary structure with gland formation in an intestinal type carcinoma (H & E, original magnification ×180).

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Figure 5. Papillary carcinoma of biliary type extending into a saccule of Beale is shown. Normal biliary epithelium is still visible (H & E, original magnification ×180).

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Three of 7 papillary carcinomas showed greater than 30% p53 positive nuclei. Likewise, MIB-1 slides from 4 tumors (4 of 7) stain between 50% and 70% nuclei.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Despite their simple histologic structure, the extrahepatic bile ducts give rise to a group of morphologically heterogenous malignant epithelial neoplasms.1, 2 Papillary carcinomas are uncommon and can originate in any segment of the extrahepatic bile ducts. In our experience, these tumors represent 4% of all malignant epithelial tumors of the extrahepatic bile ducts.1 The clinical presentation of the nine patients with papillary carcinoma of the extrahepatic bile ducts reported here is similar to that of patients with conventional adenocarcinomas, in that painless jaundice followed by abdominal pain and weight loss were the most common complaints. However, seven of the nine patients had tumors that arose in the common bile duct in contrast to more common conventional adenocarcinomas that typically arise in the upper and middle thirds of the EBD.1

Most large series of EBD carcinomas include a small number of papillary carcinomas that appear to have better prognosis.3 Unfortunately, some epidemiologic studies and surgical series do not include a detailed histologic description of the neoplasms,5 and therefore no distinction between invasive and noninvasive tumors is made in these series. Because of this, we chose to focus on the histologic features, differential diagnosis, and the morphologic features that correlate with prognosis.

Papillary carcinomas of the EBD can be classified as invasive and noninvasive and according to their cell phenotype into biliary and intestinal types. Recognition of invasion is often difficult because these tumors show expansile growth and pushing margins. This study clearly demonstrates that noninvasive and minimally invasive carcinomas of the extrahepatic bile ducts regardless of their cytologic features p53 and MIB-1 reactivity are associated with an excellent long term prognosis. None of the nine patients reported here developed recurrence or metastasis. Likewise, no patient died as a result of the tumor. This probably is related to the finding that four tumors were noninvasive and five minimally invasive carcinomas and that they were completely excised either by segmental resection with negative margins or by Whipple operations. Because the luminal component is usually larger than the minimally invading component of these papillary carcinomas, we believe that these tumors grow first toward the lumen and later invade the wall of the bile duct where they remain confined for considerable time. Therefore, histologic type and stage of disease appear to be the most important factors in the prognosis of these tumors. This conclusion is strengthened by the tumor-related death of the only patient we have observed with an invasive papillary carcinoma that extended beyond the ductal wall. The excellent prognosis of these papillary carcinomas is in sharp contrast with the poor 5-year survival rate of the most common conventional adenocarcinomas of the EBD2, 6 and therefore warrant histologic separation.

Because most of these papillary carcinomas are well differentiated and show a low mitotic rate, measurement of cell proliferation assessed by the MIB-1 antibody provides limited diagnostic information. Only 4 of 7 tumors showed a significant proportion of MIB-1 positive cells (50–70%). Likewise, 3 of 7 papillary carcinomas were positive for p53. Overexpression of p53 protein has been reported in 38–66% of invasive adenocarcinomas of the extrahepatic bile ducts.7–9 Detection of the p53 protein by immunohistochemistry correlates with gene mutation,8 but this p53 mutation that is a late event does not correlate with prognosis.8 K-ras codon 12 mutations, the most common and earliest genetic abnormality in invasive carcinoma of the extrahepatic bile ducts likewise, does not correlate with prognosis.10–13 In summary, none of the molecular markers that have been used has proven a substitute for extent of disease as a prognostic factor of carcinoma of the EBD.

A variety of lesions of the extrahepatic bile ducts that show papillary architecture should be distinguished from papillary carcinoma including papillomatosis, papillary or villous adenomas, primary papillary hyperplasia, and intraductal papillary mucinous neoplasms of the pancreas. Biliary papillomatosis is a multicentric disease that leads to multiple filling defects in several of the extrahepatic bile ducts or the entire extrahepatic biliary tree.14, 15 In some cases, the filling defects also may be observed in the intrahepatic bile ducts, gallbladder, and even the pancreatic ducts. Because of these features, biliary papillomatosis is difficult to treat and is associated with a high rate of recurrence and a poor prognosis. Most patients died 2 or 3 years after diagnosis usually as a result of septic complications. Malignant transformation occurs in 25% of the cases.14, 15 In contrast, papillary carcinoma forms a discrete, well defined polypoid lesion that obstructs the lumen of a single extrahepatic bile duct. When multicentric, small papillary lesions are observed around the main polypoid or exophytic mass. By endoscopic retrograde cholangiopancreatography, the tumor usually produces a single filling defect or is visualized as a polypoid mass that obstructs the lumen of the bile duct.

The vast majority of papillary or villous adenomas of the extrahepatic bile ducts are of intestinal type. They usually show a less complex architecture than carcinomas and are lined by columnar cells with oval hyperchromatic nuclei similar to those of colonic adenomas. Dysplastic changes are often less pronounced in adenomas than in carcinomas.2 However, adenomas that exhibit marked dysplasia often show mitotic figures and some cribriforming and the differential diagnosis may be extremely difficult especially in small biopsy samples.

Primary papillary hyperplasia of the gallbladder also may involve the cystic and common bile ducts.16 In this exceedingly rare lesion, however, the papillary structures are lined by biliary-type columnar cells without cytologic atypia.

Intraductal papillary mucinous carcinomas of the pancreas may extend into the ampulla of Vater and common bile duct simulating noninvasive papillary carcinoma.17, 18 However, intraductal papillary mucinous carcinomas of the pancreas are usually multifocal and produce abundant extracellular mucin leading to cystic dilatation of the main pancreatic duct, features that are lacking in these papillary carcinomas.

Because these papillary carcinomas behave as nonmetastasizing or in situ carcinomas, a conservative surgical approach such as segmental resection with frozen section of the surgical margins should be considered in selected cases. Extension of the tumor into the surgical margins is a powerful prognostic factor and a predictor of local recurrence.19, 20

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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