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Intrahepatic cholangiocarcinoma
Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/serndb
Intrahepatic cholangiocarcinoma Masayuki Nakano a,n, Shun-ichi Ariizumi b, Masakazu Yamamoto b a b
Division of Diagnostic Pathology, Shonan Fujisawa Tokushuukai Hospita, Japan Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan
a b s t r a c t Cholangiocarcinoma, also referred to as cholangiocellular carcinoma (particularly in Japan), develops along the biliary tract. The tumor may be intra- or extrahepatic and have different features with specific treatments based on the site of origin. Guidelines for diagnosis and management of cholangiorcarcinoma, such as those proposed by EASL (European Association for the Study of the Liver)1 and the Mayo Clinic2 classify the tumor into intrahepatic, perihilar, and distal cholangiocarcinoma. There are three main macroscopic patterns of growth of cholangiocarcinoma: mass-forming, periductal-infiltrating and intraductal. A combination of mass-forming and periductal infiltrating tumors have been shown to have a poor prognosis.3 Intrahepatic cholangiocarcinoma (ICC) comprises two microscopic subtypes: bile duct and cholangiolar.4 The bile duct subtype has tall columnar cells that form large glands, whereas cholangiolar tumors are composed of cuboidal and low columnar cells. Patients with cholangiolar tumors, referred to as cholangiolocellular carcinoma, reportedly have a better 5-year survival rate than those with the bile duct type.4 & 2017 Elsevier Inc. All rights reserved.
Case 1
Case 2
A 73-year-old man had sudden onset of epigastric pain due to cholecystitis. He had a history of drinking. Serological tests for chronic hepatitis B and hepatitis C infections were negative. A liver tumor was detected by computed tomography (CT) (Fig. 1). Laparoscopic partial hepatectomy of segment V was performed.
A 71-year-old man with diabetes mellitus and arrhythmia was noted to have abnormal liver function tests. He tested negative for hepatitis B and hepatitis C antibodies and had no history of drinking alcohol. CT imaging detected a tumor in the caudate lobe (Fig. 4). A partial hepatectomy was performed. Pathologic findings
Pathologic findings On gross examination, the resected liver specimen was seen to contain a well-demarcated, 2 cm nodule, consistent with a massforming ICC (Fig. 2A). Microscopically, the tumor was comprised of tubular structures of various sizes, many of which had dilated lumina (Fig. 3A). Many portal tracts were entrapped within the tumor (Fig. 3B).Small tubular structures were observed at periphery of the tumor (3A,3C) whereas the central part showed larger tubules. (Fig. 3A,D). The epithelium in both areas of the tumor expressed EMA (expressed epithelial membrane antigen) on the apical membranes of cancer cells (Fig. 3E and F). Diagnosis: cholangiolocellular carcinoma.
On gross examination, an irregularly shaped nodule measuring 3.5 cm in diameter with an elongated protrusion was identified consistent with a combined mass-forming and periductal-infiltrating pattern of growth. (Fig. 2B). On gross examination, the tumor was composed of irregularly shaped glands, some with an anastomosing pattern, which were lined by a single layer or stratified layer of malignant epithelial cells that showed marked nuclear pleomophism (Fig. 5A). The tumor invaded adjacent portal tracts (Fig. 5B) and appeared to extend along these to large portal tracts (Fig. 5C). Diagnosis: intrahepatic cholangiocarcinoma, combined mass forming and periductal-infiltrating type.
Case 3 n
Corresponding author. E-mail address: [email protected] (M. Nakano).
An 81-year-old man was incidentally found to have abnormal
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Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
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Fig. 1. CT scan shows a 2 cm tumor on the surface of the right lobe. This tumor shows high density in arterial phase (A), suggesting hypervascularity and low density in late portal vein dominant phase (B) and equiblium phase (C). High intensity tumor is seen on T2 MR image (D).
Fig. 2. Gross appearance of intrahepatic cholangiocarcinoma: Mass forming type (A, Case 1), combined mass forming and periductal infiltrating type (B, Case 2), periductal infiltrating type (C, Case 3) and mass forming type (D, Case 4).
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
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Fig. 3. Intrahepatic cholangiolocarcinoma made up of tubular structures which are smaller at the periphery (A,C) and larger towards the center (A,D). Many portal tracts (asterix) are trapped within the tumor (arrows) (B, Victoria Blue stain). EMA shows apical expression in the smaller (E) and larger (F) tubules. No cytoplasmic expression is seen.
liver function tests. There were no serum antibodies to hepatitis B or hepatitis C viruses and no history of drinking alcohol. CT and MRI revealed an irregular tumor in the left lobe with dilatation of the associated intrahepatic bile duct (Fig. 6). A partial hepatectomy was performed with resection of the left and caudate lobes. Pathologic findings The resected specimen contained an irregularly shaped 2 cm tumor with dilated bile ducts, indicating periductal-infiltrating type of growth pattern (Fig. 2C). Microscopic examination showed a tumor with a periductal pattern of infiltration composed of poorly formed glands (Fig. 7A). Immunohistochemistry for EMA showed expression within the cytoplasm of the malignant cells (Fig. 7B). Alcian blue PAS staining confirmed mucin production (Fig. 7C) Diagnosis: intrahepatic cholangiocarcinoma, periductal-infiltrating type.
Case 4 A 66-year-old woman was found to be anti-HCV positive. CT detected a 2.0 cm nodule which was thought to be a hemangioma. Repeat CT 6 months later revealed that the nodule had enlarged to 4.0 cm in size and appeared to be a mass-forming type of tumor (Fig. 8). The left hepatic and caudate lobes were resected. Pathologic findings The tumor measured 4.0 cm in size, was irregular in shape and associated with a satellite nodule (Fig. 2D). Microscopically, the tumor was a mass-forming ICC but not very cellular on low power (Fig. 9A, compare to 3B). Microscopically, the tumor was composed of well differentiated glands lined by a columnar epithelium which was comprised of pleomorphic cells with a high-nucleocytoplasmic ratio (Fig. 9B). The tumor demonstrated cytoplasmic expression of EMA (Fig. 9C).
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
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Fig. 4. CT scan shows an irregular 3.8 cm tumor (arrow) in the left lobe of the liver. This tumor shows low density in arterial phase (A), and delayed enhancement was seen in vein dominant phase (B). This tumor was given a diagnosis of mass form and periductal infiltating type ICC because tumor invaded the left hepatic cut on MRCP (C).
Fig. 5. Intrahepatic cholangiocarcinoma comprised of tubule-glandular structures (A) which invade the portal tracts (B, arrows),extending along these to involve a large portal tract (C, Victoria Blue stain).
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5
Fig. 6. An irregular 2 cm tumor (arrow) at left side umbilical portion, showed low density in arterial phase (A) and MRCP (C) and high intensity in portal phase (B). Dilatation of intrahepatic bile duct was seen in the left liver.
Fig. 7. Periductal-infiltrative tumor made up of poorly formed glands, including many signet ring cells (A). Tumor cells express cytoplasmic EMA (B) and mucin production is seen on Alcian blue PAS stain (C).
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
6
Fig. 8. CT scan shows an irregular 4 cm lobulated tumor in the left lobe of the liver. This tumor (arrow) shows low density in arterial phase (A), and delayed enhancement in vein dominant phase (B). Tumor appearance in size was different between sagittal and coronal views (C). This tumor was given a diagnosis of mass forming type ICC because no bile duct invasion was seen on MRCP (D).
Diagnosis: intrahepatic cholangiocarcinoma, combined mass forming type.
Discussion Cholangiocarcinoma accounts for about 15% of primary liver cancers. Its incidence varies between geographic regions; the tumor is common in Hong Kong, Southern China and Korea due endemic liver fluke infection and hepatolithiasis, which form the major risk factors for this tumor. The pathological feature common to both these diseases is chronic inflammation of the biliary tract. Chronic necro-inflammation causes increased cell turnover leading to compromised cellular repair function and accumulation of pro-carcinogenic genetic defects. The liver Cancer Study Group of Japan, has demonstrated increased positivity rate for hepatitis C in patients with ICC during four consecutive 2-year periods. It is noteworthy that some patients with cholangiocarcinoma have high serum AFP levels. Although not proven, it is conceivable that hepatic progenitor cells, which strongly express AFP, are targeted by the hepatitis C virus infection. Although the risk of metabolic syndrome in the development of hepatocellular carcinoma is well documented, there are only limited studies investigating its impact on the development of cholangiocarcinoma. An outbreak of cholangiocarcinoma was reported among workers in an offset color printing press at a printing company in Japan. Retrospective study revealed that these individuals were exposed to chemicals including dichlorometan and 1,2-dichloropropan, which might therefore represent risk factors for
development of cholangiocarcinoma. The gross appearance of ICC differs according to the growth and invasion pattern. The cut surface of the tumor commonly reveals a white, hard mass, due to the presence of abundant fibrous stroma (Fig. 2). The histological appearance of the tubulo-glandular adenocarcinoma varies according to the degree of differentiation and origin within the biliary tree.4 There may be a higher proportion of columnar or cuboidal epithelium. Cholangiolocellular carcinoma is a very rare carcinoma that shows features suggestive of cholangiolar differentiation. There is also the view that it originates from cholangioles and has features of both hepatocellular carcinoma and cholangiocarcinoma. Although this tumor has been reported multiple times in literature, our knowledge about its characteristics is limited. In our experience, pure cholangiolocellular carcinoma has a better outcome than ICC. In our experience, all cholangiolocellular carcinomas demonstrated a mass forming growth pattern Clinical imaging Representative images of ICC on arterial-phase computed tomography (CT) show a mass with low-attenuation.5 On MRI, the signal intensity of the edge of the tumor is predominantly low on T1-weighted images in most cases. The signal intensity is high on T2-weighted images in most cases.6 Cholangiolocellular carcinoma exhibits imaging features similar to those of ICC, but early as well as persistent delayed enhancement is a characteristic imaging finding of this rare tumor.7,8
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
7
Fig. 9. Intrahepatic cholangiocarcinoma (arrows mark border of the tumor) infiltrating into portal tracts which are fewer in number than seen in cholangiolocellular carcinoma (A, Victoria Blue stain, compare with Fig. 3B). Tumor is composed of well differentiated glands lined by a columnar epithelium of pleomorphic cells with a highnucleocytoplasmic ratio (B). The tumor demonstrates cytoplasmic expression of EMA (C).
Immunohistochemistry and histochemistry ICC is immunohistochemically positive for the biliary keratins, K7 and K19. Immunostaining for EMA, which is expressed by epithelial cells of glands and ducts, most commonly demonstrates cytoplasmic and apical luminal immunoreactivity. The pattern of EMA staining differentiates between bile duct epithelium and cholangioles, thus allowing the distinction of ICC from cholangiocellular carcinoma, which is important because of the differing prognosis of these two tumors.7 Whereas ICC expresses EMA within the cytoplasm of tumor cells, this antigen is only expressed on the apical membranes of tumors cells of cholangiolocellular carcinoma (Case 1). Mucin production detected by Alcian blue PAS stain is seen in ICC but not in cholangiolocellular carcinoma (Case 3). Victoria blue (VB) is a specific stain for elastic fibers. In the normal liver, only the portal tracts stain positively with VB. As VB delineates the exact location of the portal tract, it is very helpful as a histologic marker for clarifying the hepatic structure and diagnosing liver diseases. Prognostic factors and treatment The prognosis of cholangiocarcinoma remains very poor. Macroscopic and microscopic features have been shown to influence prognosis. The 5-year survival rate is better for the mass forming type of ICC (44%) than for the periductal infiltrating type (27%). Well-differentiated tumors have a better prognosis than moderately to poorly differentiated tumors. Cholangiolocellular carcinoma, composed of very well differentiated tubules, when occurring in a pure form has a
better prognosis than the ductal type of ICC. However, most often, this variant is associated with hepatocellular carcinoma or ICC, when it assumes the prognosis of the associated tumor. Hepatic resection offers the only hope for long-term survival and is curative in a select number of patients. Radiation, especially stereotactic body radio therapy (SBRT), proton beam therapy, carbon-ion radiotherapy, as well as sorafenib based chemotherapy, have been used in selected patients. Local recurrence occurs frequently.
References 1. Bridgewater John, Gall Peter R, Khan Shahid A, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268– 1289. 2. Razumilava Nataliya, Gores Grgory J. Classificarion, diagnosis, and managemnent of cholangiocarcinoma. [e4]. Clin Gastroenrerol Hepatol 2013;11:13 [e4]. 3. Yamamoto Masakazu, Takasaki Ken, Yoshikawa Tatsuya, et al. Does gross appearance indicate prognosis in intrahepatic cholangiocarcinoma? J Surg Oncol 1998;69:162–167. 4. Lian Jau-Yu, Tasi Jia-Huei, Yuan Ray-Hwang, et al. Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol 2014;27:1163–1173. 5. Han Jook Koo, Choi Byung Ihn, et al. Cholangiocarcinoma: pictorial essay of CT and cholangiographic findings. Radiographics 2002;22:173–187. 6. Yoji Maetani Kyo, Itoh Chihiro Watanabe, et al. MR Imaging of intrahepatic cholangiocarcinoma with pathologic correlation. AJR 2001;176:1499–1507. 7. Arizumi Shun-ichi, Kotera Yoshihito, Katagiri Satoshi, et al. Long-term survival of patients with cholangiocellular carcinoma after curative hepatectomy. Ann Surg Oncol 2014;21(Suppl 3):451–458. 8. Motosugi Utarou, Ichikawa Takaaki, Nakajima H, et al. Cholangiocellular carcinoma of the liver: imaging findings. J Comput Assist Tomogr 2009;33:682–688.
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
Contents lists available at ScienceDirect
Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/serndb
Intrahepatic cholangiocarcinoma Masayuki Nakano a,n, Shun-ichi Ariizumi b, Masakazu Yamamoto b a b
Division of Diagnostic Pathology, Shonan Fujisawa Tokushuukai Hospita, Japan Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Japan
a b s t r a c t Cholangiocarcinoma, also referred to as cholangiocellular carcinoma (particularly in Japan), develops along the biliary tract. The tumor may be intra- or extrahepatic and have different features with specific treatments based on the site of origin. Guidelines for diagnosis and management of cholangiorcarcinoma, such as those proposed by EASL (European Association for the Study of the Liver)1 and the Mayo Clinic2 classify the tumor into intrahepatic, perihilar, and distal cholangiocarcinoma. There are three main macroscopic patterns of growth of cholangiocarcinoma: mass-forming, periductal-infiltrating and intraductal. A combination of mass-forming and periductal infiltrating tumors have been shown to have a poor prognosis.3 Intrahepatic cholangiocarcinoma (ICC) comprises two microscopic subtypes: bile duct and cholangiolar.4 The bile duct subtype has tall columnar cells that form large glands, whereas cholangiolar tumors are composed of cuboidal and low columnar cells. Patients with cholangiolar tumors, referred to as cholangiolocellular carcinoma, reportedly have a better 5-year survival rate than those with the bile duct type.4 & 2017 Elsevier Inc. All rights reserved.
Case 1
Case 2
A 73-year-old man had sudden onset of epigastric pain due to cholecystitis. He had a history of drinking. Serological tests for chronic hepatitis B and hepatitis C infections were negative. A liver tumor was detected by computed tomography (CT) (Fig. 1). Laparoscopic partial hepatectomy of segment V was performed.
A 71-year-old man with diabetes mellitus and arrhythmia was noted to have abnormal liver function tests. He tested negative for hepatitis B and hepatitis C antibodies and had no history of drinking alcohol. CT imaging detected a tumor in the caudate lobe (Fig. 4). A partial hepatectomy was performed. Pathologic findings
Pathologic findings On gross examination, the resected liver specimen was seen to contain a well-demarcated, 2 cm nodule, consistent with a massforming ICC (Fig. 2A). Microscopically, the tumor was comprised of tubular structures of various sizes, many of which had dilated lumina (Fig. 3A). Many portal tracts were entrapped within the tumor (Fig. 3B).Small tubular structures were observed at periphery of the tumor (3A,3C) whereas the central part showed larger tubules. (Fig. 3A,D). The epithelium in both areas of the tumor expressed EMA (expressed epithelial membrane antigen) on the apical membranes of cancer cells (Fig. 3E and F). Diagnosis: cholangiolocellular carcinoma.
On gross examination, an irregularly shaped nodule measuring 3.5 cm in diameter with an elongated protrusion was identified consistent with a combined mass-forming and periductal-infiltrating pattern of growth. (Fig. 2B). On gross examination, the tumor was composed of irregularly shaped glands, some with an anastomosing pattern, which were lined by a single layer or stratified layer of malignant epithelial cells that showed marked nuclear pleomophism (Fig. 5A). The tumor invaded adjacent portal tracts (Fig. 5B) and appeared to extend along these to large portal tracts (Fig. 5C). Diagnosis: intrahepatic cholangiocarcinoma, combined mass forming and periductal-infiltrating type.
Case 3 n
Corresponding author. E-mail address: [email protected] (M. Nakano).
An 81-year-old man was incidentally found to have abnormal
http://dx.doi.org/10.1053/j.semdp.2016.12.012 0740-2570/& 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
2
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Fig. 1. CT scan shows a 2 cm tumor on the surface of the right lobe. This tumor shows high density in arterial phase (A), suggesting hypervascularity and low density in late portal vein dominant phase (B) and equiblium phase (C). High intensity tumor is seen on T2 MR image (D).
Fig. 2. Gross appearance of intrahepatic cholangiocarcinoma: Mass forming type (A, Case 1), combined mass forming and periductal infiltrating type (B, Case 2), periductal infiltrating type (C, Case 3) and mass forming type (D, Case 4).
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
Fig. 3. Intrahepatic cholangiolocarcinoma made up of tubular structures which are smaller at the periphery (A,C) and larger towards the center (A,D). Many portal tracts (asterix) are trapped within the tumor (arrows) (B, Victoria Blue stain). EMA shows apical expression in the smaller (E) and larger (F) tubules. No cytoplasmic expression is seen.
liver function tests. There were no serum antibodies to hepatitis B or hepatitis C viruses and no history of drinking alcohol. CT and MRI revealed an irregular tumor in the left lobe with dilatation of the associated intrahepatic bile duct (Fig. 6). A partial hepatectomy was performed with resection of the left and caudate lobes. Pathologic findings The resected specimen contained an irregularly shaped 2 cm tumor with dilated bile ducts, indicating periductal-infiltrating type of growth pattern (Fig. 2C). Microscopic examination showed a tumor with a periductal pattern of infiltration composed of poorly formed glands (Fig. 7A). Immunohistochemistry for EMA showed expression within the cytoplasm of the malignant cells (Fig. 7B). Alcian blue PAS staining confirmed mucin production (Fig. 7C) Diagnosis: intrahepatic cholangiocarcinoma, periductal-infiltrating type.
Case 4 A 66-year-old woman was found to be anti-HCV positive. CT detected a 2.0 cm nodule which was thought to be a hemangioma. Repeat CT 6 months later revealed that the nodule had enlarged to 4.0 cm in size and appeared to be a mass-forming type of tumor (Fig. 8). The left hepatic and caudate lobes were resected. Pathologic findings The tumor measured 4.0 cm in size, was irregular in shape and associated with a satellite nodule (Fig. 2D). Microscopically, the tumor was a mass-forming ICC but not very cellular on low power (Fig. 9A, compare to 3B). Microscopically, the tumor was composed of well differentiated glands lined by a columnar epithelium which was comprised of pleomorphic cells with a high-nucleocytoplasmic ratio (Fig. 9B). The tumor demonstrated cytoplasmic expression of EMA (Fig. 9C).
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
4
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Fig. 4. CT scan shows an irregular 3.8 cm tumor (arrow) in the left lobe of the liver. This tumor shows low density in arterial phase (A), and delayed enhancement was seen in vein dominant phase (B). This tumor was given a diagnosis of mass form and periductal infiltating type ICC because tumor invaded the left hepatic cut on MRCP (C).
Fig. 5. Intrahepatic cholangiocarcinoma comprised of tubule-glandular structures (A) which invade the portal tracts (B, arrows),extending along these to involve a large portal tract (C, Victoria Blue stain).
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
5
Fig. 6. An irregular 2 cm tumor (arrow) at left side umbilical portion, showed low density in arterial phase (A) and MRCP (C) and high intensity in portal phase (B). Dilatation of intrahepatic bile duct was seen in the left liver.
Fig. 7. Periductal-infiltrative tumor made up of poorly formed glands, including many signet ring cells (A). Tumor cells express cytoplasmic EMA (B) and mucin production is seen on Alcian blue PAS stain (C).
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
6
Fig. 8. CT scan shows an irregular 4 cm lobulated tumor in the left lobe of the liver. This tumor (arrow) shows low density in arterial phase (A), and delayed enhancement in vein dominant phase (B). Tumor appearance in size was different between sagittal and coronal views (C). This tumor was given a diagnosis of mass forming type ICC because no bile duct invasion was seen on MRCP (D).
Diagnosis: intrahepatic cholangiocarcinoma, combined mass forming type.
Discussion Cholangiocarcinoma accounts for about 15% of primary liver cancers. Its incidence varies between geographic regions; the tumor is common in Hong Kong, Southern China and Korea due endemic liver fluke infection and hepatolithiasis, which form the major risk factors for this tumor. The pathological feature common to both these diseases is chronic inflammation of the biliary tract. Chronic necro-inflammation causes increased cell turnover leading to compromised cellular repair function and accumulation of pro-carcinogenic genetic defects. The liver Cancer Study Group of Japan, has demonstrated increased positivity rate for hepatitis C in patients with ICC during four consecutive 2-year periods. It is noteworthy that some patients with cholangiocarcinoma have high serum AFP levels. Although not proven, it is conceivable that hepatic progenitor cells, which strongly express AFP, are targeted by the hepatitis C virus infection. Although the risk of metabolic syndrome in the development of hepatocellular carcinoma is well documented, there are only limited studies investigating its impact on the development of cholangiocarcinoma. An outbreak of cholangiocarcinoma was reported among workers in an offset color printing press at a printing company in Japan. Retrospective study revealed that these individuals were exposed to chemicals including dichlorometan and 1,2-dichloropropan, which might therefore represent risk factors for
development of cholangiocarcinoma. The gross appearance of ICC differs according to the growth and invasion pattern. The cut surface of the tumor commonly reveals a white, hard mass, due to the presence of abundant fibrous stroma (Fig. 2). The histological appearance of the tubulo-glandular adenocarcinoma varies according to the degree of differentiation and origin within the biliary tree.4 There may be a higher proportion of columnar or cuboidal epithelium. Cholangiolocellular carcinoma is a very rare carcinoma that shows features suggestive of cholangiolar differentiation. There is also the view that it originates from cholangioles and has features of both hepatocellular carcinoma and cholangiocarcinoma. Although this tumor has been reported multiple times in literature, our knowledge about its characteristics is limited. In our experience, pure cholangiolocellular carcinoma has a better outcome than ICC. In our experience, all cholangiolocellular carcinomas demonstrated a mass forming growth pattern Clinical imaging Representative images of ICC on arterial-phase computed tomography (CT) show a mass with low-attenuation.5 On MRI, the signal intensity of the edge of the tumor is predominantly low on T1-weighted images in most cases. The signal intensity is high on T2-weighted images in most cases.6 Cholangiolocellular carcinoma exhibits imaging features similar to those of ICC, but early as well as persistent delayed enhancement is a characteristic imaging finding of this rare tumor.7,8
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i
M. Nakano et al. / Seminars in Diagnostic Pathology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
7
Fig. 9. Intrahepatic cholangiocarcinoma (arrows mark border of the tumor) infiltrating into portal tracts which are fewer in number than seen in cholangiolocellular carcinoma (A, Victoria Blue stain, compare with Fig. 3B). Tumor is composed of well differentiated glands lined by a columnar epithelium of pleomorphic cells with a highnucleocytoplasmic ratio (B). The tumor demonstrates cytoplasmic expression of EMA (C).
Immunohistochemistry and histochemistry ICC is immunohistochemically positive for the biliary keratins, K7 and K19. Immunostaining for EMA, which is expressed by epithelial cells of glands and ducts, most commonly demonstrates cytoplasmic and apical luminal immunoreactivity. The pattern of EMA staining differentiates between bile duct epithelium and cholangioles, thus allowing the distinction of ICC from cholangiocellular carcinoma, which is important because of the differing prognosis of these two tumors.7 Whereas ICC expresses EMA within the cytoplasm of tumor cells, this antigen is only expressed on the apical membranes of tumors cells of cholangiolocellular carcinoma (Case 1). Mucin production detected by Alcian blue PAS stain is seen in ICC but not in cholangiolocellular carcinoma (Case 3). Victoria blue (VB) is a specific stain for elastic fibers. In the normal liver, only the portal tracts stain positively with VB. As VB delineates the exact location of the portal tract, it is very helpful as a histologic marker for clarifying the hepatic structure and diagnosing liver diseases. Prognostic factors and treatment The prognosis of cholangiocarcinoma remains very poor. Macroscopic and microscopic features have been shown to influence prognosis. The 5-year survival rate is better for the mass forming type of ICC (44%) than for the periductal infiltrating type (27%). Well-differentiated tumors have a better prognosis than moderately to poorly differentiated tumors. Cholangiolocellular carcinoma, composed of very well differentiated tubules, when occurring in a pure form has a
better prognosis than the ductal type of ICC. However, most often, this variant is associated with hepatocellular carcinoma or ICC, when it assumes the prognosis of the associated tumor. Hepatic resection offers the only hope for long-term survival and is curative in a select number of patients. Radiation, especially stereotactic body radio therapy (SBRT), proton beam therapy, carbon-ion radiotherapy, as well as sorafenib based chemotherapy, have been used in selected patients. Local recurrence occurs frequently.
References 1. Bridgewater John, Gall Peter R, Khan Shahid A, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268– 1289. 2. Razumilava Nataliya, Gores Grgory J. Classificarion, diagnosis, and managemnent of cholangiocarcinoma. [e4]. Clin Gastroenrerol Hepatol 2013;11:13 [e4]. 3. Yamamoto Masakazu, Takasaki Ken, Yoshikawa Tatsuya, et al. Does gross appearance indicate prognosis in intrahepatic cholangiocarcinoma? J Surg Oncol 1998;69:162–167. 4. Lian Jau-Yu, Tasi Jia-Huei, Yuan Ray-Hwang, et al. Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol 2014;27:1163–1173. 5. Han Jook Koo, Choi Byung Ihn, et al. Cholangiocarcinoma: pictorial essay of CT and cholangiographic findings. Radiographics 2002;22:173–187. 6. Yoji Maetani Kyo, Itoh Chihiro Watanabe, et al. MR Imaging of intrahepatic cholangiocarcinoma with pathologic correlation. AJR 2001;176:1499–1507. 7. Arizumi Shun-ichi, Kotera Yoshihito, Katagiri Satoshi, et al. Long-term survival of patients with cholangiocellular carcinoma after curative hepatectomy. Ann Surg Oncol 2014;21(Suppl 3):451–458. 8. Motosugi Utarou, Ichikawa Takaaki, Nakajima H, et al. Cholangiocellular carcinoma of the liver: imaging findings. J Comput Assist Tomogr 2009;33:682–688.
Please cite this article as: Nakano M, et al. (2017), http://dx.doi.org/10.1053/j.semdp.2016.12.012i