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Japanese Journal of Clinical Oncology

Intrahepatic Cholangiocarcinoma Presenting Intrabile Duct Extension: Clinicopathologic Study of Five Resected Cases
Introduction
Subjects and Methods
Results
Discussion
References

Intrahepatic Cholangiocarcinoma Presenting Intrabile Duct Extension: Clinicopathologic Study of Five Resected Cases

Intrahepatic Cholangiocarcinoma Presenting Intrabile Duct Extension: Clinicopathologic Study of Five Resected Cases Junji Yamamoto1, Tomoo Kosuge1, Tadatoshi Takayama1, Kazuaki Shimada1, Susumu Yamasaki1, Michiie Sakamoto2, Setsuo Hirohashi2 and Masatoshi Makuuchi3

1Department of Surgery, National Cancer Center Hospital, 2 Pathology Division, National Cancer Center Research Institute, Tokyo and 3Second Department of Surgery, University of Tokyo Faculty of Medicine, Tokyo, Japan

Intrahepatic cholangiocarcinoma, which is ordinarily a very invasive tumor and often takes a rapid and fatal course, sometimes shows macroscopic intrabile duct extension. The purpose of this study is to illustrate the clinicopathologic features of this variant of intrahepatic cholangiocarcinoma, which has occasionally been reported. Five cases of the tumor with gross extension to the bile duct lumen were studied to determine their clinical and pathologic features. The tumor showed intrabile duct growth and superficial mucosal spread in two patients. In two other patients, an apparent mass lesion accompanied the intraluminal component. In the remaining patient, a polypoid tumor infiltrated the portal tract of the left lateral segment, where it had arisen. Microscopic examination did not reveal any vascular involvement or intrahepatic or lymph node metastasis. All of the patients are alive without recurrence, except for Patient l who died 7 years and 7 months after surgery from a rapidly growing tumor in the liver remnant. Intrabile duct growth of intrahepatic cholangiocarcinoma may reflect indolent biological behavior and thus warrants an aggressive surgical approach, which appears to give a good prognosis.

Key words: intrahepatic cholangiocarcinoma - intrabile duct extension - surgery - prognosis - pathology

Introduction

Intrahepatic cholangiocarcinoma (ICC), which reportedly is associated with limited resectability and a poor prognosis, sometimes shows intrabile duct extension (1,2). Although there have been few reported cases, intraductal papillary ICC is of low-grade malignancy and thus merits surgical treatment (3). We present here five patients with ICC showing intraluminal growth and discuss the clinicopathologic features of this variant of ICC.

Subjects and Methods

Between January 1980 and March 1994, 837 patients underwent hepatectomy for primary liver cancer at the National Cancer Center Hospital, Tokyo. Of these, 27 were found histopathologically to have ICC. In five patients with ICC, the tumor showed intrabile duct growth. These patients consisted of four women and one man, with an average age of 64.8 yr (range 52-77 yr). For each patient, demographic data, gross and microscopic pathologic findings of the tumors, treatment and results were reviewed. Macroscopically, the location based on the anatomy of the bile duct system, size and gross extension pattern of each tumor were recorded. Each segment or segmental bile duct was numbered according to Couinaud (4). Microscopic examination consisted of histologic differentiation, the intrahepatic spreading pattern of the tumor [vascular involvement, invasion of the connective tissue of the portal tract, lymphatic involvement, perineural invasion, superficial extension replacing the biliary epithelium (5)] and the presence of cancer cells at the surgical margin.

Results

Two patients were found to have the disease through the presence of jaundice. Patient 1 had an episode of jaundice (max. serum total bilirubin = 6.2 mg/dl) which lasted five days. Patient 4 developed jaundice (max. serum total bilirubin = 16.8 mg/dl) due to a protruding intraductal tumor from the left hepatic duct into the common bile duct. In patient 2, a pedunculated tumor obstructing the outlet of duct B3 caused relapsing febrile attack and right hypochondralgia (Table 1). Limited dilatation of the intrahepatic bile duct was found in all of the patients. However, intrabile duct tumor was diagnosed in only two patients, for whom cholangiography was performed percutaneously or endoscopically (Patient 1 and Patient 4).

The affected hepatic lobe was treated by resection or extended resection (Table 1). Three patients underwent excision of the extrahepatic bile duct with bilioenteric reconstruction. The lymph nodes around the hepatoduodenal ligament were dissected in all of the patients.

Schemata of the gross tumor appearance and extension are shown in Fig.1. In Patients 1, 2, and 5, the intraductal lesion formed the main body of the tumor (Fig. 2), while in Patients 3 and 4, intraluminal extension was accompanied by a mass-forming main tumor. In the former cases, a polypoid lesion was attached to the bile duct just at the orifice of the segmental duct: the anterior segmental duct in Patient 1, B3 in Patient 2 and the confluence of B2 and B3 in Patient 5. In the lesions which formed a mass (Patients 3 and 4), the site at which the tumor had broken the wall into the bile duct could not be determined. The tumors in Patients 1 and 2 consisted of mucosal spreading carcinoma, which was not macroscopically recognized. Such intramucosal spread appeared to be confined to the segmental duct distal to the polypoid tumor: the anterior segmental duct in Patient 1, and B3 and B4 in Patient 2 (Fig. 1).

The histologic type of the tumors was either papillary or well-differentiated adenocarcinoma [Fig. 3(a),(b)]. The polypoid component in Patient 2 was composed of well-differentiated squamous cell carcinoma with a very thin stalk, forming an adenosquamous carcinoma (Table 2). There was no evidence of biliary papillomatosis. None of the tumors showed microscopic vascular invasion. Even in the portal tract invaded by a parenchymal mass lesion, adenocarcinoma did not infiltrate the adjacent vascular structures. Invasion of the lymphatics and nerves of the portal tract was seen in two Patients (3 and 5). In Patient 5, the tumor showed these invasive features at the confluence of B2 and B3, where the polypoid lesion originated (Fig. 1). There was no evidence of lymph node metastasis.


Figure 1. Schematic presentation of each Patient. The origin and size of each tumor is noted. Dilated intrahepatic bile ducts are depicted by a scalloped contour. A thickened bile duct wall represents the superficial spread of cholangiocarcinoma. In Patient 5, the hatched area represents infiltration of adenocarcinoma into the connective tissue of the portal tract. *segments numbered according to Coinaud (4); SCC, squamous cell carcinoma; AC, adenocarcinoma.


Figure 2. The polypoid tumor (1.5 *1.2 cm) in Patient 1, which originated at the orifice of the anterior segmental duct.

Table 1Clinical features, treatment and results
Patient no. Age and sex Signs and symptoms Surgery Outcome, time since surgery
1

 52F

 Transient jaundice
epigastralgia		 Right lobectomy
bile duct excision		 Dead
7 yr 7 mo
2

 77F

 Relapsing fever
hypochondralgia		 Left lobectomy

 Alive and well
3 yr 7 mo
3

 68M

 No symptoms

 Extended
left lobectomy		 Alive and well
3 yr 1 mo
4


 70F


 Jaundice


 Extended
left lobectomy
bile duct excision		 Alive and well
2 yr 4 mo
5


 57F


 No symptoms


 Left lobectomy
bile duct excision

 Alive and well
2 yr 1 mo

Table 2. Microscopic features of cholangiocarcinoma showing intrabile duct growth
Patient no.


 Histologic type



 Vascular
involvment


Lymphatic
involvment


Perineural
invasion


Superficial replacing
growth of biliary epithelium
1

 Papillary
adenocarcinoma		 no

 no

 no

 yes
2



 Adenosquamous carcinoma
(well differentiated
tubular adenocarcinoma and squamous cell carcinoma)
 no



 no



 no



 yes
3

 Well differentiated
tubular adenocarcinoma		 no

 no

 yes (slight)

 no
4

 Well differentiated
tubular adenocarcinoma		 no

 no

 no

 no
5

 Papillary
adenocarcinoma		 no

 yes (slight)

 yes (slight)

 no

Patient 1 died 7 yr 7 mo after surgery, from a rapidly growing tumor in the remnant liver. There had been no evidence of recurrence 7 yr after surgery, but three months later, elevated serum carcinoembryonic antigen level (44.3 µg/ml, normal value <5 µg/ml) and right pleural effusion were noted. Hepatic angiography disclosed a massive hypervascular tumor 9*7 cm in diameter in the remnant liver. She showed rapid deterioration and died from hepatic failure. The histology of the tumor was not examined.

Patients 2, 3, 4 and 5 are all alive 3 yr 7mo, 3 yr 1 mo, 2 yr 4 mo and 2 yr1 mo respectively after surgery, without recurrence at the time of writing (Table 2).

Discussion


Figure 3. (a) Papillary adenocarcinoma of intraductal component in Patient 5. (b) Well differentiated tubular adenocarcinoma of the mass lesion in Patient 3.
Intraductally growing ICC is a relatively rare disease and there are few reported cases (1-3). We encountered five resected cases (18.5%) of ICC showing intraluminal growth among 27 Patients with ICC in the past 15 years. Thus intraductal growth is not a rare form of extension in resectable ICC. The extension mode of ICC can be categorized into three macroscopic types: (1) expansive growth in the hepatic parenchyma; (2) infiltrative extension along the portal tract; and (3) polypoid stretching in the lumen of the bile duct (6,7). The gross appearance of an individual tumor presents a combination of these modes of growth. In the present series, each tumor showed a different combination of extension modes, and they appeared to be very different forms of ICC.

From a clinicopathologic perspective, the intraductal component caused pathognomonic symptoms of malignancy in three of the five patients, and all of the patients showed elevated serum alkaline phosphatase. Endoscopically or percutaneously conducted cholangiography was useful for preoperative diagnosis of the intrabile duct tumor. Mucobilia, which is often seen in patients with papillary ICCs and causes episodic jaundice and abdominal pain, was not observed in our series. Thus the transient jaundice seen in Patient 1 might have been due to some other cause(s), such as floating tumor debris (6)

A salient feature of the ICCs in the present series is the less invasive biological behavior of the tumors, compared to that of ordinary ICC (5,7-11) Neither intrahepatic nor distant metastasis was observed. Microscopic vascular invasion was also not observed, even in a portal tract invaded by a mass lesion. Although lymphatic and perineural invasion, which is frequently observed in ordinary ICCs (5,7-11), was seen in two Patients, its degree was slight and dissected lymph nodes were all cancer-free. In our previous report on 20 resected ICCs, vascular involvement was found in 50%, intrahepatic metastasis in 35%, and lymph node metastasis in 25% (11).

In hepatocellular carcinoma (HCC), intrabile duct tumor growth indicates that the tumor has a propensity for invasive biological behavior. HCC with intrabile duct tumor growth is frequently accompanied by a tumor thrombus in the portal vein, and runs a rapidly fatal course (12). On the other hand, as our series of patients suggested, extension into the bile duct reflects a less invasive ICC, even if the tumor seems parenchymal in origin. Since the tumor extends mainly into the bile duct lumen, jaundice or other obstructive symptoms are not necessarily harbingers of advanced disease.

Ordinary ICC is reported as presenting a poor prognosis, even if resected (13-16). Post resection recurrence often develops within a year (11). By contrast, all of our Patients are alive without recurrence, except for Patient 1 who died 7 yr 7 mo after surgery. Intrabile duct progression, if observed in a patient with ICC, warrants aggressive surgical therapy and appears to give a good prognosis.

References

1. Iyomasa S, Nimura Y, Kamiya J, Maeda S, Kondo S, Yasui A et al. Cholangiocellular carcinoma in the caudate lobe with intraluminal growth in the extrahepatic bile duct. Hepato-Gastroenterology 1992;39:570-3. MEDLINE Abstract

2. Styne P, Warren GH, Kumpe DA, Halgrimson C, Kern Jr. F. Obstructive cholangitis secondary to mucus secreted by a solitary papillary bile duct tumor. Gastroenterology 1986;90:748-53. MEDLINE Abstract

3. Capizzi PJ, Rosen CB, Nagorney DM. Intermittent jaundice by tumor emboli from intrahepatic cholangiocarcinoma. Gastroenterology 1992;103;1669-73. MEDLINE Abstract

4. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris. Masson et Cie.1957.

5. Nakajima T, Kondo Y, Miyazaki M, Okui K. A histopathologic study of 102 cases of intrahepatic cholangiocarcinoma: histologic classification and modes of spreading. Hum Pathol 1988;19:1228-34. MEDLINE Abstract

6. Roslyn JJ, Kuchenbecker S, Longmire WP, Tompkins RK. Floating tumor debris: a cause of intermittent biliary obstruction. Arch Surg 1984;119: 1312-15. MEDLINE Abstract

7. Edmondson HA. Tumor of the liver and intrahepatic bile ducts. In: Atlas of Tumor Pathology, Series 7, Fascicle 25. Washington, DC: Armed Forces Institute of Pathology 1958;109.

8. Nakanuma Y, Minato H, Kida T, Terada T. Pathology of cholangiocellular carcinoma. In: T. Tobe, H. Kameda et al., editors. Primary Liver Cancer in Japan. Tokyo, Berlin, Heidelberg, New York, London, Paris, Hong Kong, Barcelona: Springer-Verlag, 1992;39-50.

9. Nakajima T, Kondo Y. A clinicopathologic study of intrahepatic cholangiocarcinoma containing a component of squamous cell carcinoma. Cancer 1990;65:1401-4. MEDLINE Abstract

10. Weinbren K, Mutum SS. Pathological aspects of cholangiocarcinoma. J Pathol 1983;139:217-29. MEDLINE Abstract

11. Yamamoto J, Kosuge T, Takayama T, Shimada K, Makuuchi M, Yoshida J et al. Surgical treatment of intrahepatic cholangiocarcinoma: four Patients surviving more than five years. Surgery 1992;111:617-22. MEDLINE Abstract

12. Kojiro M, Kawabata K, Kawano Y, Shirai F, Takemoto N, Nakashima T. Hepatocellular carcinoma presenting as intrabile duct tumor growth: a clinicopathologic study of 24 cases. Cancer 1982;49:2144-7. MEDLINE Abstract

13. Rockwell G, Barker JW, Lasersohn JT. Cholangiocarcinoma of the liver: Case report with seven-year survival, with review of the literature on primary liver tumors and hepatic resections. Cancer 1966;19:1177-84. MEDLINE Abstract

14. Sanguily J, Calderin VO. Partial resection of the liver for primary cholangiocarcinoma: presentation of a successful case. Am J Surg 1974;128: 603-7. MEDLINE Abstract

15. Kawarada Y, Mizumoto R. Cholangiocellular carcinoma of the liver. Am J Surg 1984;147:354-9. MEDLINE Abstract

16. Chen M-F, Jan Y-Y, Wang C-S, Jeng L-B, Hwang T-L. Clinical experience in 20 hepatic resections for peripheral cholangiocarcinoma. Cancer 1989;64: 2226-32. MEDLINE Abstract

Received May 27, 1996; revised September 2, 1996
For reprints and all correspomdence: Junji Yamamoto, Department of Surgery, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan
Abbreviations: ICC, Intrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma

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Copyright© Japanese Journal of Clinical Oncology, 1997.
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