Hepatic intraductal oncocytic papillary carcinoma

Authors


Abstract

BACKGROUND

There has been an increasing incidence and mortality from peripheral cholangiocarcinoma (PC) in the United States over the past 24 years. PC has been classified into two principal types, a mass-forming type and a periductal-infiltrating type, with a significant difference in the clinical behavior between the two. A third type, demonstrating a noninvasive intraductal growth of PC, was described as papillary PC. Rarely, papillary hepatic tumors composed of oncocytic cells have been described. Intraductal oncocytic papillary carcinomas (IOPCs) of the liver present as large, mucin-filled, cystic lesions lined by noninvasive or focally microinvasive oncocytic tumors.

METHODS

From June 1999 to August 2001, three patients with hepatic IOPCs were identified in the files of the Hepatobiliary Service, Department of Surgery, and the Department of Pathology at Memorial Sloan-Kettering Cancer Center. They form the basis of this study. We report the clinicopathologic presentation, as well as the outcome, with a review of the literature.

RESULTS

All three cases presented with well defined intrahepatic cystic masses ranging in size from 7.2 to 21.1 cm. The most prominent cells of the lining epithelium were columnar with oncocytic features showing abundant eosinophilic granular cytoplasm and centrally located nucleoli. All three patients underwent resection with one demonstrating local bile duct recurrence that was managed with stenting. Review of the literature has identified 39 patients with papillary PC and 2 patients with IOPC. The biology of these reported cases has been variable with overall survival better than that of nonpapillary PC patients, with recurrence in 15% of the reported cases.

CONCLUSION

Papillary PC is a rare type of cholangiocarcinoma that includes an interesting variant: IOPC. These tumors are predominantly found in men, who present with large (> 5 cm) mucinous cystic lesions of the bile duct. A noninvasive histology is seen, and long-term survival may be achieved with complete resection. Invasive variants of IOPC have been reported in the literature and have a worse overall prognosis. Cancer 2002;95:2180–7. © 2002 American Cancer Society.

DOI 10.1002/cncr.10934

Hilar and peripheral cholangiocarcinomas (PC) are the second most common types of primary hepatic malignancy. There has been an increasing incidence and mortality from PC in the United States over the past 24 years.1 As with the more common hilar cholangiocarcinoma, complete resection of PC can result in long-term survival2 and is the only effective therapy.3 PC has been classified into two principal types, a mass-forming type and a periductal-infiltrating type, with a significant difference in the clinical behavior between the two.4 A third type, demonstrating a noninvasive intraductal growth of PC, was described as papillary PC5 (Fig. 1). This tumor has a papillary growth pattern and may be associated with intraductal mucin accumulation. Twenty-eight cases of intraductal papillary PC of the liver have been reported in the literature.6–11 Reports have suggested a less aggressive tumor biology, with potential long-term survival, but the rarity of these tumors has limited information on outcome.

Figure 1.

Three types of peripheral cholangiocarcinoma. (a) Mass forming. (b) Periductal. (c) Papillary intraductal.

Most papillary cholangiocarcinomas exhibit variably complex intraductal papillae lined by cells resembling either the normal biliary epithelium or the pseudostratified columnar cells of intestinal adenomas. Rarely, papillary hepatic tumors composed of oncocytic cells have been described.12, 13 This growth pattern is very similar to that of intraductal oncocytic papillary carcinoma (IOPC) of the pancreas,14 which has been recognized as a variant of intraductal papillary-mucinous neoplasms distinct from other primary pancreatic tumors. Intraductal oncocytic papillary carcinomas of the pancreas exhibit mucin-filled cystic ducts, with a predominantly intraductal, noninvasive growth pattern. There is a similar presentation to IOPCs of the liver. Patients present with large, mucin-filled, cystic lesions lined by noninvasive or focally microinvasive oncocytic tumors.

In this study, we report our experience with three patients with IOPC, as well as review the reported cases from the literature of both IOPC and intraductal papillary PC.

MATERIALS AND METHODS

From June 1999 to August 2001, three patients with hepatic IOPCs were identified in the files of the Hepatobiliary Service, Department of Surgery, and the Department of Pathology at Memorial Sloan-Kettering Cancer Center. They form the basis of this report. The presenting clinical symptoms, operative procedures, and postoperative outcomes were reviewed.

The pathology of the resected tumors was studied and the gross configuration, microscopic growth patterns, and cytologic features were recorded. The presence and extent of an invasive carcinoma was noted. A variety of immunohistochemical stains were performed using the antibodies listed in Table 1 employed with standard immunohistochemical techniques. In situ hybridization for albumin mRNA was also performed using previously described methodology.15

Table 1. Antibodies Utilized for Immunohistochemical Staining
AntibodySourceDilutionPretreatment
  1. CEA: carcinoembryonic antigen.

CK7Dako (Carpinteria, CA)1:20,000Pronase
CK20Dako1:1000Protease 24
CK19Dako1:1000Citrate
CEA (polyclonal)Dako1:500Citrate
CA125Signet (Dedham, MA)1:200Citrate
CA19.9Signet1:4000Pepsin
B72.3Biogenix (San Ramon, CA)1:500Citrate
DU-PAN2Biogenix1:1Citrate
ChromograninDako1:8000Citrate
SynaptophysinBoehringer Mannheim (Indianapolis, IN)1:20Citrate
p53 (DO7)Dako1:500Citrate
Ki67Immunotech (Miami, FL)1:100Citrate
113-1Biogenix1:50Pronase
α-FetoproteinDako1:20,000Citrate
HepPar1Dako1:500Citrate

RESULTS

Clinical Findings

The clinical data are summarized in Table 2. The first patient was a 46-year-old man who presented to an outside hospital with a 5-year history of intermittent right upper abdominal pain and rigors. This patient underwent imaging and was found to have a cystic lesion centrally located in the liver. He underwent exploration and cyst unroofing at a referring center, and was then transferred to Memorial Sloan-Kettering Cancer Center. Laboratory values at the time of transfer included a bilirubin of 4.4, alkaline phosphatase of 302, aspartate aminotransferase (AST) of 102, and alanine aminotranferse (ALT) of 101. Imaging demonstrated a large residual septated cystic mass occupying the caudate lobe, with marked extrahepatic and intrahepatic ductal dilation (Fig. 2a). The patient underwent reexploration, hilar lymphadenectomy, and left lobectomy with caudate lobe resection. The tumor recurred at the biliary anastomosis of the right hepatic duct. The patient is alive with disease at last follow-up, 3 years after resection.

Table 2. Clinicopathologic Features of Three Patients Treated at Memorial Sloan-Kettering Cancer Center for IOPC
CaseGenderAge (yrs)SiteCT/MRI findingsSize (cm)Follow-up (mos)
  1. IOPC: intraductal oncocytic papillary carcinoma; CT: computed tomographic scan; MRI: magnetic resonance imaging; IHD: intrahepatic ductal dilation.

1Male50Left lobeCystic mass21.16
2Male46Left lobeCystic mass with IHD21.030
3Male38Right lobeIHD7.28
Figure 2.

(A) T2-weighted magnetic resonance image (MRI) scan, axial view, demonstrating a hyperintense, predominantly cystic mass in Segment 1 of the liver with extension and compression of adjacent hepatic parenchyma. The mass has peripheral intermediate signal intensity and nodularity. (B) T2-weighted MRI scan, axial view, demonstrating a hyperintense, predominantly cystic lesion (arrows) with an area of intermediate intensity mass (M) within the cystic lesion. (C) Axial computed tomographic scan demonstrating a predominantly cystic mass occupying the left lobe of the liver with soft tissue nodularity (arrows) along the border.

The second patient is a 39-year-old man who presented with a single episode of painless jaundice that resolved spontaneously. Radiographic imaging demonstrated a lobulated enhancing mass with biliary ductal dilation and atrophy of Segments 5 and 8 (Fig. 2B). Laboratory values demonstrated a bilirubin of 0.5, alkaline phosphatase of 389, AST of 28, and ALT of 56. This patient underwent exploration and extended right hepatectomy and was free of disease at a follow-up of 2 years.

The third patient is a 50-year-old man who presented with vague abdominal pain and a palpable abdominal mass. Radiographic workup demonstrated a large cystic mass in the left lobe of the liver, with biliary ductal dilation (Fig. 2C). Laboratory values demonstrated a bilirubin of 0.4, alkaline phosphatase of 50, AST of 21, and ALT of 19. He underwent left hepatectomy and was free of disease at 18 months follow-up.

Pathologic Findings

All three cases appeared grossly as well defined cystic masses ranging from 7.2 to 21.1 cm (Fig. 3). Although intimate involvement of the bile ducts was not easily appreciated, tumor was identified grossly within dilated bile ducts in two of the cases. The cyst contents were mucoid and hemorrhagic. The cyst walls and septa were lined with soft and friable papillary tumor masses with focally nodular, more solid areas. The cyst walls were smooth in other areas. The tumor growth was grossly confined within the cyst walls without any evidence of invasion into the adjacent liver parenchyma. The adjacent nonneoplastic liver parenchyma was grossly unremarkable. The microscopic findings in the three cases were similar. The tumors were largely exophytic into the cyst lumina and showed variable degrees of architectural complexity, ranging from sparse filiform papillae to a more exuberant growth giving rise to solid areas with slit-like spaces (Fig. 4). Fibrovascular cores were mostly well formed and composed of loosely textured stroma with myxoid change and lymphoplasmacytic infiltrates. The most predominant cells of the lining epithelium were columnar cells with oncocytic features showing abundant eosinophilic granular cytoplasm and centrally located nuclei with prominent nucleoli (Fig. 5). Other cells had basally located nuclei with apical mucinous cytoplasm and resembled the gastric foveolar epithelium. Scattered goblet cells were also present. A distinctive feature was the presence of intraepithelial mucin-containing lumina that gave rise to a cribriform pattern (Fig. 5a). The epithelium ranged from a simple cuboidal to columnar epithelium to areas of stratified epithelium with loss of polarization. Cellular clusters were budding from the papillae lined by multilayered epithelium. Cytologic atypia ranged from mild to moderate. Mitoses were present and the mitotic count ranged from 1 to 3 per 10 high power fields in most areas.

Figure 3.

Gross appearance of a 21-cm cystic tumor filled with mucin and soft brown mural nodules. Direct communication with the bile ducts is difficult to appreciate grossly.

Figure 4.

(A) Microscopically, the tumors consist of massively dilated bile ducts lined by exuberant papillary projections. The papillae are complex and focally fused. (B) Extension of tumor into smaller bile duct.

Figure 5.

(A) At higher power, the complexity of the papillae is more evident. The lining epithelium is cribriformed and exhibits both intraepithelial and intracellular lumina. (B) Cytologically, the tumor cells contain abundant eosinophilic cytoplasm and large, central nuclei with prominent nucleoli.

In all cases, communication with the duct system was histologically confirmed. Elements of tumor extended beyond the gross tumor capsule into dilated peripheral bile ducts. A transition between the tumoral epithelium and the nonneoplastic epithelium of the bile ducts was identified. In one case, there was a minimal focus of invasive carcinoma extending into the cyst wall without invasion of liver parenchyma. The resection margins were free of tumor in all cases.

The results of immunohistochemical staining are listed in Table 3. The keratin profile of these tumors was CK7 positive, CK19 positive, and CK20 negative. The 113-1 antibody against mitochondria was positive in all cases. Most glycoproteins (carcinoembryonic antigen [CEA], CA125, and CA19.9) were not expressed, although B72.3 was found in all three cases. One tumor had a minor endocrine cell component. There was no staining for α-fetoprotein (AFP) and the polyclonal antibody against CEA failed to reveal a canalicular staining pattern. The hepatocyte-specific antibody, HepPar1, was positive in all cases. The Ki67 antibody revealed a low proliferative rate (10–20%). In situ hybridization for albumin mRNA was negative in all three cases.

Table 3. Results of Immunohistochemical Staining in Three Cases and One Case Report
StainCase 1Case 2Case 3Sudo et al.16
  1. F: focal; AFP: α-fetoprotein.

CK7F(−)F(+)
CK20(−)(−)(−)(−)
CK19(+)(+)(+)(+)
CEA (polyclonal)(−)(−)(−)(−)
CA125(−)(−)(−)ND
CA19.9(−)(−)(−)(−)
B72.3(+)(+)(+)ND
DUPAN2(−)(−)FND
ChomograninF(−)(−)ND
SynaptophysinF(−)(−)ND
p53(−)(−)(−)ND
Ki6720%15%10%ND
113-1(+)(+)(+)(+)
AFP(−)(−)(−)(−)
HepPar1(+)(+)(+)(+)
Albumin (in situ hybridization)(−)(−)(−)(−)

Papillary PC: A Review of the Literature

There have been six reports of 39 patients with papillary PC.6–11 Three reports of 26 patients with complete clinical data and follow-up were available for review (Table 4). A median age of 55 years and a greater incidence among men (68%) was seen. The site of primary was evenly distributed between the right and left lobes of the liver, with all patients presenting with localized disease only. The mean tumor size was 4.3 cm and pain was the most common presenting symptom.

Table 4. Demographics of All Reported Cases of Papillary Peripheral Cholangiocarcinoma in the English Literature (n = 26)
Gender 
 Males17
 Females9
Mean age (yrs) (range)55 (38–73)
Mean tumor size (cm) (range)4.3 (1.0–21.1)
Location 
 Right lobe12
 Left lobe14
Symptoms 
 Pain10
 Jaundice8
 Palpable mass3
 Weight loss1
 None4

Of the 26 patients for whom complete clinical and follow- up data were available, 4 (13%) had documented recurrences at a mean interval of 1 year. The most common location was intrahepatic.

IOPC: A Review of the Literature

There have been two previous reports of IOPCs of the liver.12, 13 One patient presented with carcinomatosis, never underwent resection, and died of progressive disease. The diagnosis was confirmed at autopsy. The other patient was diagnosed after resection, but the tumor recurred. This patient died 25 months from initial diagnosis. Both of these reports were confirmed pathologically, but differ from our three reported cases by the aggressive biology.

DISCUSSION

Primary adenocarcinoma arising from the intrahepatic bile ducts, or PC, is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC).17, 18 The clinicopathologic characteristics of PC are distinct from HCC and hilar cholangiocarcinoma. For example, PC is not associated with chronic liver disease and infrequently gives rise to jaundice. Complete resection remains the only effective treatment.

The reported survival rate of patients with PC ranges from a very poor 5year survival of 15%19 to a greater than 50% survival rate.17 The reason for the differences in survival may be related to variability in the classification of PC because a number of subtypes exist with differing prognoses (Fig. 1). Yamamoto et al.4 classified PC into two types, a mass-forming type and a periductal-infiltrating variant, with significant differences in clinical behavior. The mass-forming type demonstrated an obvious hepatic mass with a higher incidence of local recurrence following resection. The periductal type more commonly caused a stricture or obstruction of the hepatic ducts without a definite mass within the liver. The periductal type was also more likely to have portal lymph node metastasis.

The third type of PC, in which the tumor demonstrates a noninvasive papillary growth into the lumen of the bile duct, is the least common variant of PC.5 Although there have been few reports of small numbers of patients with papillary PC, a better outcome following resection has been suggested.7, 8 The three cases presented in the current study represent an unusual variant of papillary PC in which the neoplastic cells have an oncocytic appearance. Only two earlier cases of IOPC have been reported.12, 13 They shared with the current cases a cystic gross configuration and a markedly complex microscopic architecture.

Although there are insufficient cases of IOPC from which to draw firm conclusions about biologic behavior, the features appear to be similar to those of papillary PCs in general. A review of all reported cases demonstrated papillary PC to be more common in men in the sixth decade of life (Table 3). This distribution is similar to that of Jarnagin et al.20 In their experience with hilar cholangiocarcinoma, they reported an incidence of 55% in males and a median age of 68 years. The size of papillary PCs has varied among the reported cases, ranging from 4 to 22 cm. This difference is directly related to the location of the primary lesion, with more proximal tumors producing earlier biliary ductal obstruction and thus earlier symptoms. Patients with lesions in the peripheral biliary tree often present with much larger mucin-filled cysts (Fig. 2). The most common presenting symptoms are abdominal pain and jaundice, primarily because of the intraductal growth and the obstruction of the intrahepatic ducts. Liver enzymes as well as hepatitis screens have been nonspecific in this patient population.

Recurrences from papillary PC have been uncommon (5 of 26 reported cases or 11%), with one patient presenting with advanced disease. A noninvasive histology has been reported in most cases and lymph node metastases have not been reported. Peritoneal seeding is rare even in the face of fluid spillage. In one of our cases, the cyst had been unroofed at primary operation at an outside facility, but the peritoneum was free of disease at definitive operation 5 months later. The patient has remained free of disease at 2-year follow-up. The overall survival of the patient population is very favorable, with both large reported series having a 5-year survival rate in excess of 80%.7, 8 Presumably, the favorable prognosis reflects the absence of a significant invasive component. In one of our cases, there was a small component of invasive carcinoma extending beyond the cystic ducts, but the majority (95%) of the tumor remained exophytic and noninvasive. The noninvasive histology also results in large lesions that often require large hepatic resections. The cystic configuration of papillary PCs (and IOPCs in particular) results from dilatation of involved bile ducts,12 although a transition from the papillary tumor to the nonneoplastic bile duct epithelium may be difficult to demonstrate in some cases. The cystic nature of papillary PCs is similar to the appearance of hepatobiliary cystadenocarcinomas. Hepatobiliary cystadenocarcinomas arise as benign hepatobiliary cystadenomas from which invasive carcinoma develops. They commonly exhibit hypercellular ovarian-like stroma, a finding absent in papillary PCs and useful in their diagnosis.

Relative to most papillary PCs, the oncocytic variant reported here is more cystic appearing and histologically more complex. The oncocytic cytoplasm is distinctive. Glycoprotein markers commonly detected in papillary cholangiocarcinomas (CEA, CA19.9, CA125) are absent in IOPCs; only B72.3 is expressed. The eosinophilic cytoplasm raises the possibility of hepatocellular differentiation, as suggested in one previously reported case.12 All of our cases, as well as the example reported by Sudo et al.,16 were immunohistochemically positive for HepPar1, a putative marker of hepatocellular differentiation.21, 22 However, the antigen identified by this antibody remains unknown. Somestudies have questioned the specificity of HepPar1 staining,23, 24 showing frequent positivity in gastric adenocarcinomas, for instance. In our cases, other markers of hepatocellular differentiation (CEA, AFP) were negative and the positive staining found for B72.3 and CK19 in the majority of tumor cells strongly argues against a true hepatocellular neoplasm. Most importantly, we were unable to detect albumin mRNA by in situ hybridization, a technique reportedly to be most sensitive and specific for detecting hepatocellular differentiation.15 The staining for HepPar1 is intriguing, but currently its significance for hepatocellular differentiation is uncertain.

We believe the eosinophilic cytoplasm reflects an abundance of mitochondria, as in other truly oncocytic tumors. An analogy exists between papillary tumors of the bile ducts and pancreas. In the pancreas, intraductal papillary-mucinous neoplasms25–28 are similar to papillary PCs, and intraductal oncocytic papillary neoplasms26 are nearly identical to hepatic IOPCs.

To conclude, papillary PC is a rare type of cholangiocarcinoma that includes an interesting variant, IOPC. These tumors are predominantly found in men, who present with large (> 5 cm) mucinous cystic lesions of the bile duct. A predominantly noninvasive pattern is seen and long-term survival may be achieved with complete resection. Invasive variants have been reported in the literature with a worse overall prognosis.

Ancillary