INTRODUCTION

Cholangiolocellular carcinoma (CLC) is an ex-tremely rare malignant liver tumor which was firstdefined by Steiner, et al . in 1957 (1). CLC is thoughtto be derived from Hering’s canal because tumorglands of CLC are morphologically similar to cho-langioles. Hering’s canals are found in portal tractsof all sizes where they connect with the bile duct.

The small cells of Hering’s canal have a basementmembrane like the more distal portions of the bili-ary tree but an apical surface that appears similar tohepatic canalicular membrane. Recently, Theise, etal . reported that Hering’s canal might be composedof hepatic stem cells (2). In addition, CLC sometimescontain a HCC or CCC component within a tumor.Those findings suggest that CLC might originatefrom hepatic stem cells. On the other hand, because

CASE REPORT

Cholangiolocellular carcinoma containing hepatocellularcarcinoma and cholangiocellular carcinoma, extremelyrare tumor of the liver : a case report

Mami Kanamoto1), Tomoharu Yoshizumi1), Toru Ikegami1), Satoru Imura1),

Yuji Morine1), Tetsuya Ikemoto1), Nobuya Sano2), and Mitsuo Shimada1)

1)Department of Digestive and Pediatric Surgery, and 2)Department of Pathology, Institute of Health

Biosciences The University of Tokushima Graduate School, Tokushima, Japan

Abstract : Cholangiolocellular carcinoma (CLC) is an extremely rare malignant liver tu-mor which was first defined by Steiner, et al . in 1957 (1). CLC is thought to be derivedfrom Hering’s canal because tumor glands of CLC are morphologically similar to cholan-gioles. Recently, Theise, et al . reported that Hering’s canal might be composed of hepaticstem cells (3). In addition, CLC sometimes contains a hepatocellular carcinoma (HCC) orcholangiocellular carcinoma (CCC) component within the tumor. Those findings suggestthat CLC might originate from hepatic stem cells. On the other hand, because of its lowfrequency, clinicopatholigical features of CLC have not been fully clarified yet. We hereinreport a case of a 71-year old man with CLC. Based on preoperative imagings, the hepatictumor was diagnosed as HCC, and he underwent a partial hepatectomy. The tumor con-tained both a HCC and CCC-like area. In immunohistochemistry, cytokeratin (CK) 7, CK20,CAM5.2 was positive, and CK19 was negative, therefore the tumor was diagnosed as CLC.The diagnostic criteria have not been described clearly, so CLC is difficult to diagnosepreoperatively. Further studies are needed to clarify the clinical and clinicopatholigicalfeatures of CLC. J. Med. Invest. 55 : 161-165, February, 2008

Keywords : a rare tumor of the liver , cholangiocellular carcinoma, cholangiolocellular carcinoma, hepatic stemcell , hepatocellular carcinoma

Abbreviations : CLC, cholangiolocellular carcinoma ; HCC, he-patocellular carcinoma ; CCC, cholangiocellular carcinoma ; CEA,carcinoembryonic antigen ; AFP, alpha fetoprotein ; CK, cytokera-tin ; CA19-9, carbohydrate antigen 19-9 ; PIVKA-II, protein inducedby vitamin K absence-II ; HCV, hepatitis C virus ; HBV, hepatitisB virus ; CTAP, computed tomography during arterial portogra-phy ; CTA, computed tomography angiography ; SPIO, super-paramagnetic iron oxide

Received for publication October 22, 2007 ; accepted November14, 2007.

Address correspondence and reprint requests to Mitsuo ShimadaM.D., FACS, Department of Digestive and Pediatric Surgery,Institute of Health Biosciences, The University of TokushimaGraduate School, Kuramoto-cho, Tokushima 770-8503, Japan andFax : +81-88-631-9698.

The Journal of Medical Investigation Vol. 55 2008

161

of its low frequency, clinicopatholigical features ofCLC have not been clarified as yet. Moreover, fewcases have been reported in English literature. Weherein present a case of CLC with its imagings andclinicopatholigical findings, and review the litera-ture, especially focusing on hepatic stem cell origin.

CASE REPORT

A 71-year old man with chronic hepatitis C wasreferred for an evaluation of an asymptomatic livermass that was detected by routine abdominal ultra-sonography. Serum biochemistry and tumor mark-ers, such as carcinoembryonic antigen (CEA), al-pha fetoprotein (AFP), AFP-L 3%, carbohydrate an-tigen (CA) 19-9, and protein induced by vitamin Kabsence-II (PIVKA-II) were within normal range(Table 1). The early phase of enhanced computedtomography (CT) showed marked enhancement ofthe tumor that measured approximately 1.0�1.0 cmin the right lobe of the liver (Fig. 1). The tumor hadhomogeneous enhancement on delayed CT. Themargin of the tumor was not clear. On T1- weightedmagnetic resonance imagings (MRIs), the tumorwas low intensity, whereas, on T2 with high inten-sity. On superparamagnetic iron oxide (SPIO) - en-hanced liver MRIs, the tumor had marked enhance-ment with contrast material. On common hepaticangiography, the entire tumor showed hypervascu-larity, and pooling on the delayed images. Computedtomography angiography (CTA) showed the highdensity tumor. On computed tomography duringarterial portography (CTAP) images, only the pe-ripheral lesion of the tumor was enhanced.

Based on those preoperative imagings, the he-patic tumor was diagnosed to be HCC. The patient

underwent a partial hepatectomy and liver cirrho-sis was unclear. The tumor was felt in the right lobeof the liver, which was approximately 1.5 cm, elas-tic hard, and moved well.

The resected tumor was measured 10�15 mm,whitish in color, solid, not encapsulated, and hadan irregular margin (Fig. 2). Histological findingsrevealed that small ductules showing anastomos-

Table 1. Laboratory findings

WBCRBCHGBHCTPLTPT

GOTGPTALPLDHg-GTPTPALB

5300/ml396�104/ml13.1g/ml39.5%25.7�10/ml11.0s

28 IU/L19 IU/L138 U/L157 U/L67 U/L7.3g/dl3.9g/dl

BUNCre

ICG-R 15

CEACA19-9PIVKA-IIAFP

Hbs AgHbc AbHCV AbHCV-RNA

12mg/dl0.81mg/dl

13%

1.4ng/L9U/ml10 mAU/ml6U/ml

(-)(-)(+)(-)

AA BB

CC DD

EE FF

Fig. 1. (A) A hepatic arterial-phase computed tomography(CT) shows marked enhancement of the tumor that measuredapproximately 1.0�1.0 cm in the right lobe of the liver. (B) Aportal-phase scan. (C) A delayed-phase scan shows a homoge-neous hyper attenuating tumor. (D) T1- weighted magnetic reso-nance imaging (MRI), the tumor is low intensity. (E) T2-weighted MRI shows the tumor high intensity. (F) Superparamag-netic iron oxide (SPIO) - enhanced liver MRI show the tumormarked enhancement with contrast material.

M. Kanamoto, et al. cholangiolocellular carcinoma of the liver162

ing pattern, and composing of a moniliform struc-ture. Tumor cells proliferated and replaced the sur-rounding normal tissue. In small areas of the tumor,relatively big ductules were detected and resem-bled cholangiocellular carcinoma. Furthermore, thetumor contained hepatocellular carcinoma (HCC)-

like area. In immunohistochemistry, cytokeratin(CK) 7, CK20, CAM5.2 was positive in a part ofHCC, and CK19 was negative in CLCs (Fig. 3). C-kit was positive in part. The patient’s postoperativerecovery was uneventful and he has been doing wellfor 12 months after the operation.

AA

BB

CC

DD

Fig. 3. Immunohistochemistry shows the tumor was positivefor Cytokeratin (CK) 7 (A), CAM 5.2 (B), and negative for CK19 (C). Tumor cells express c-kit (D).

AA

BB

CC

Fig. 2. (A) Macroscopic finding. The tumor is measured10�15mm and whitish in color, solid, not encapsulated, andhas irregular margin. (B, C) Microscopic findings. Small duc-tules show anastomosing pattern, and compose of moniliformstructure. In focal area of the tumor, relatively big ductules aredetected and resembled cholangiocellular carcinoma (B). Fur-thermore, the tumor contained an HCC-like area (C). (Hema-toxylin and eosin stains. A :�100, B :�200).

The Journal of Medical Investigation Vol. 55 February 2008 163

DISCUSSION

CLC is an extremely rare primary malignant tu-mor in the liver, and the frequency is as low as0.56% in Japan (3). Because of its low frequency,clinicopatholigical features of CLC have not beenclarified. The clinicopatholigical characteristics andfindings of images were studied on 9 cases of CLCwhose clinical courses were reported in Japan (3,4). Five of these 9 patients (56%) were infectedwith HCV, one (11%) was infected with HBV, and3 (33%) were negative for both HCV antibody andHBs antigen (Table 2). This suggests that CLC hassome association with chronic hepatitis, especiallyHCV antibody positive (3). Moreover, because manycases were infected with HCV or HBV, CLC hadbeen often mistaken as HCC clinically. MRI wasperformed on 4 cases, and tumors showed high in-tensity on T1-weighted MRIs and low intensity onT2-weighted MRIs in all 4 cases. Angiography wasperformed on 7 cases. In 6 cases, the entire tumorshowed hypervascularity. This finding suggests thathypervascularity is one of the characteristics of CLC.

In many cases, tumors were macroscopically whit-ish in color (5). Gross appearance of these tumorsresembled CCC. Two cases contained CLC compo-nent only in histological findings. In the other 3cases, tumors had HCC components, and another

had CCC components. In the other 3 cases includ-ing our case, tumors had both components. Hepaticstem cells, which have the potential to differentiateinto either hepatocytes or cholangio cells, have beenthought to be cholangioles composing Hering’s ca-nals (6). Because CLC are thought to be derivedfrom Hering’s canal, CLC is suggested to have plu-ripotency to proliferate into HCC and/or CCC. Inthis case, the tumor has an HCC-like area or CCC-like area. In addition, c-kit which is positive in im-mature cells was positive in this case (7, 8). Thisfindings support the scenario that CLC is derivedfrom hepatic stem cells. On the other hand, CK19,which is positive in normal cholangio cells, wasnegative in this tumor (9-12). These findings sug-gest that expressions of keratin in the tumor mighthave changed in the process of carcinogenesis. CK19was positive in HCC-like area of the tumor, andCAM, which is usually expressed on HCC, was posi-tive as well. These findings suggest that the tumorcells were derived from CLC which can differenti-ate into either HCC or CCC.

The prognosis of CLC was reported to be betterthan HCC. A case who survived for 6 years withoutrecurrence was reported. However, the prognosisof CLC is not stated clearly yet, because of its lowerfrequency.

The diagnosis criteria on imaging have not been

Table 2. Clinicopatholigical features of CLC cases reported in Japan

case age/sex virus enhancement in

CT MRI angiography pathology/immunohistochemistry prognosis

No. 1 69/ M HCV mosaic T1 : low hyper- HCC, CCC combined 36 Months

T2 : high vascularity CK 7 (+) alive

No. 2 67/ M HBV periphery (+) hyper- CLC 33 Months

vascularity CK 7, 19(+) dead

No. 3 61/ M (-) mosaic hyper- HCC combined 40 Months

vascularity CEA, CA 19-9 (+) alive

No. 4 68/ M HCV mosaic hyper- HCC combined 14 Months

vascularity CEA (+) dead

No. 5 61/ M HCV mosaic hyper- CLC 72 Months

vascularity CEA (+) alive

No. 6 63/ F HCV periphery (+) T1 : low no findings HCC reduplicated 18 Months

T2 : high alive

No. 7 54/ F (-) periphery (+) T1 : low CCC combined 3 Months

T2 : high CK 7 (+), CA 19-9 (+) alive

No. 8 58/ M (-) not enhanced HCC, CCC combined 1 Month

CK 7 (+) dead

No. 9 71/ M HCV mosaic T1 : low hyper- HCC, CCC combined 6 Months

T2 : high vascularity CK 7, 20 (+) alive

HCV : hepatitis C virus HBV : hepatitis B virus

M. Kanamoto, et al. cholangiolocellular carcinoma of the liver164

described clearly, so CLC is difficult to diagnose pre-operatively. Further studies are needed to clarify theclinical and clinicopatholigical features of CLC.

REFERENCES

1. Steiner PE : Carcinoma of liver in United States.Acta Unio internat. Contra Cancrum 13 : 628-645, 1957

2. Theise ND, Saxena R, Portmann BC, ThungSN, Yee H, Chiriboga L, Kumar A, CrawfordJM : The canals of hering and hepatic stem cellsin humans. Hepatology 30 : 1425-1433, 1999

3. Shiota K, Taguchi J, Nakashima O, NakashimaM, Kojiro M : Clinicopathologic study on Cho-langiolocellular carcinoma, Oncology Reports8 : 263-268, 2001

4. Yamamoto M, Takasaki K, Nakano M, Saito A :Hepatic Recurrence of Cholangiocellular carci-noma : Report of a case, Hepato-Gastroenterol-ogy 43 : 1046-1050, 1996

5. Fukuoka Y, Hamanoue M, Fujiyoshi F, SasakiM, Haruta K, Inoue H, Aiko T, Nakajo M :Cholangiolocellular Carinoma of the Liver : CTand MR findings J Comput Assist Tomogr 24 :809-812, 2000

6. Steiner PE, Higginson J : Cholangiolocellularcarcinoma of the liver. Cancer 12 : 753-759, 1959

7. Nomoto K, Tsuneyama K, Cheng C, TakahashiH, Hori R, Murai Y, Takano Y : Intrahepaticcholangiocarcinoma arising in cirrhotic liverfrequently expressed p63-positive basal/stem-cell phenotype, Pathol Res Pract 202 : 71-76,2006

8. Stroescu C, Herlea V, Dragnea A, Popescu I :

The Diagnostic Value of Cytokeratins and Car-cinoembryonic Antigen Immunostaining in Dif-ferentiating Hepatocellular Carcinomas fromIntrahepatic Cholangiocarcinomas, J Gastro-intest Liver Dis 15 : 9-14, 2006

9. Uenishi T, Kubo S, Hirohashi K, Yamamoto T,Ogawa M, Tanaka H, Shuto T, Kinoshita H :Expression of bile duct-type cytokeratin in non-cancerous hepatocytes in patients with hepati-tis B virus-related hepatocellular carcinoma,Hepatogastroenterology 50 : 1101-4, 2003

10. James J, Lygidalis NJ, van Eyken P, Tanka AK,Bosch KS, Ramaekers FC, DesmerV : Appli-cation of keratin immunocytochemistry andsirius red staining in evaluating intrahepaticchanges with acute extrahepatic cholestasisdue to hepatic duct carcinoma, Hepatogastro-enterology 36 : 151-5, 1989

11. Uenishi T, Hirohashi K, Shuto T, TsukamotoT, Yamamoto T, Ogawa M, Kubo S, Tanaka H,Kinoshita H : Primary liver cancer with dualexpression of hepatocyte and bile duct epithe-lial markers, Hepatogastroenterology 49 : 1092-4, 2002

12. Tanaka S, Hirohashi K, Uenishi T, Yamamoto T,Hamba H, Kubo S, Tanaka H, Shuto T, OgawaM, Kinoshita H : A mixed hepatocellular car-cinoma and cholangiocarcinoma : dual expres-sion of biliary-type cytokeratin and hepatocytespecific marker, Hepatogastroenterology 51 :839-41, 2004

13. Cha I, Cartwright D, Guis M, Miller TR, FerrellLD : Angiomyolipoma of the liver in fine-needleaspiration biopsies : its distinction from hepa-tocellular carcinoma, Cancer 87 : 25-30, 1999

The Journal of Medical Investigation Vol. 55 February 2008 165