Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Successful local treatment for repeated hepatic recurrences of cholangiolocellular carcinoma: a report on a long-term survivor

Successful local treatment for repeated hepatic recurrences of cholangiolocellular carcinoma: a... Background: Cholangiolocellular carcinoma (CoCC) is a rare liver tumor arising from the canals of Hering found between the cholangioles and interlobular bile ducts. Although morphologically CoCC mimics intrahepatic cholangiocarcinoma (ICC), CoCC exhibits a unique intermediate biologic behavior between hepatocellular carcinoma (HCC) and ICC. Curative resection is required for prolonged survival in patients with CoCC. However, effective therapy for postoperative hepatic recurrence has not yet been standardized. Case presentation: A 40-year-old man had an asymptomatic liver mass found during a regular medical examination. Contrast-enhanced computed tomography revealed a well-enhanced mass, 15 cm in diameter, in the right liver. He underwent right hemihepatectomy at a local hospital under the preoperative diagnosis of hepatocellular carcinoma. Pathologic examination confirmed a moderately differentiated tubular adenocarcinoma, leading to a diagnosis of ordinary ICC. Twelve months after surgery, he was referred to our hospital due to three hepatic recurrences in the left medial segment. He underwent partial hepatectomy for the recurrence, followed by adjuvant chemotherapy using gemcitabine alone. After the second hepatectomy, hepatic recurrences developed an additional seven times. The numbers and sizes of the recurrent tumors were very limited at each recurrence, satisfying the standard criteria for percutaneous radiofrequency ablation (RFA) for the treatment of HCC. All lesions were treated by percutaneous RFA, although this was an exceptional approach for ICC. He is now alive without evidence of disease 9.2 years after the first hepatectomy. Because his clinical outcome was satisfactory and not compatible with the typical negative outcomes of ordinary ICC, we re-reviewed the histological findings of his tumor. The tumor was composed of small gland-forming cells proliferating in an anastomosing pattern; the cell membrane was strongly immunoreactive for epithelial membrane antigen. These findings were in accordance with the typical features of CoCC, revising his final diagnosis from ICC to CoCC. Conclusions: This case report demonstrates a satisfactory outcome using repeated local treatments, such as hepatectomy and RFA, for hepatic recurrences of CoCC, suggesting that a localized treatment approach can be considered to be a therapeutic option. We should be careful in making a definitive diagnosis of ICC and ruling out CoCC because the diagnosis potentially dictates the treatment strategy for recurrences. Keywords: Radiofrequency ablation, Intrahepatic recurrence, Intrahepatic cholangiocarcinoma, Cholangiolocellular carcinoma * Correspondence: nagino@med.nagoya-u.ac.jp Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Shinohara et al. Surgical Case Reports (2017) 3:120 Page 2 of 6 Background history of chronic hepatitis or fatty liver. Serum tumor Cholangiolocellular carcinoma (CoCC) is a rare primary markers were increased; the patient’s protein induced by liver tumor and was first described by Steiner et al. in vitamin K absence or antagonist-II (PIVKA-II) level was 1959 [1]. This tumor is histologically characterized by 2737 mAU/ml, and his alpha-fetoprotein (AFP) level was small gland-forming tumor cells with variable extents of 23,054 ng/ml. The patient’s serum carbohydrate antigen fibrous stroma. The morphologic features of CoCC resem- 19-9 (CA19-9) level was not measured. Contrast- ble those of the canals of Hering, intervening between the enhanced CT revealed a well-enhanced mass, 15 cm in cholangioles and interlobular bile ducts. However, until re- diameter, in the right liver without extrahepatic lesion cently, this disease had been categorized as a variant of or- (Fig. 1). He underwent right hemihepatectomy without dinary intrahepatic cholangiocarcinoma (ICC) [2]. Theise lymph node dissection under the preoperative diagnosis of et al. observed that the canals of Hering potentially di- HCC (Fig. 2). Histologically, a moderately differentiated verge to hepatocytes and cholangiocytes [3]. Thus, CoCC tubular adenocarcinoma was found, leading to a patho- has an intermediate tumor biology between hepatocellular logic diagnosis of ICC. According to the American Joint carcinoma (HCC) and ICC [4] and is considered to be an Committee on Cancer (7th edition) [7], this tumor was independent disease [5]. classified as pT1NXM0 and R0 resection was achieved. It is well known that CoCC has favorable survival out- An abdominal CT performed 12 months after surgery comes after curative resection [6]. However, because of revealed three hyper vascular tumors in the left medial the rarity of CoCC, clinical outcomes in patients who re- segment (S4), the size of which ranged from 8 to 26 mm lapse remain poorly understood. Herein, we describe a (Fig. 3). He was referred to our hospital, and a partial long-term survivor who had frequent recurrences of hepatectomy of S4 was performed. The liver transection CoCC that were treated by hepatectomy and radiofre- margin was positive (R1 resection) because one tumor quency ablation (RFA). This is the first report showing was adjacent to the umbilical portion of the left the potential utility of RFA for recurrent CoCC. portal vein. The operation time was 337 min, and the blood loss was 637 ml. He had a satisfactory postop- Case presentation erative course and was discharged on postoperative A 40-year-old Japanese man presented to a local hospital day 14. Pathologically, the recurrent tumors were for evaluation of an asymptomatic liver mass detected similar to the primary lesion, leading to a diagnosis of during a regular medical examination. He had no medical recurrent ICC. Fig. 1 Computed tomography images. a Arterial-phase scan shows a peripherally well-enhanced tumor in the right liver (arrow) with vessel penetration (arrow head). Retention of the contrast media in the lesion is observed b from portal phase c to delayed phase Shinohara et al. Surgical Case Reports (2017) 3:120 Page 3 of 6 2 months for surveillance. In total, he developed hepatic recurrences an additional seven times following the sec- ond hepatectomy, and a total of 10 recurrent tumors in all were treated by percutaneous RFA (Fig. 4; Table 1). He is now alive without evidence of disease 9.2 years after the first hepatectomy and 4.7 years after the last RFA. Because his clinical course was not compatible with the usual negative course observed in patients with post- operative liver metastasis of ordinary ICC, we re- reviewed the histological findings of the initial recurrent lesions. The histological slides of the primary tumor were not available. Surprisingly, several specific features of CoCC were found: small-sized gland formation, pro- liferation in an anastomosing pattern, gradual transition to naive hepatocytes, and no mucin production (Fig. 4), while the portal vein area was not found within the tumor. The tumor contained neither ICC-like nor HCC-like areas. Immunohistochemically, the tumor cells Fig. 2 Gross finding of the primary lesion. Cut surface of the tumor were positive for cytokeratin 7 and 19 and negative for shows a yellowish nodule 13 cm in diameter neural cell adhesion molecule (NCAM), HepPar1, and S100P. Epithelial membrane antigen (EMA) was strongly The patient received adjuvant chemotherapy with gem- positive at the apical membrane of the tumor cells citabine alone (the sole regimen for biliary tract cancer (Fig. 5). All these findings, except for negative immuno- that the Japanese national insurance system allowed at the reaction of NCAM, strongly supported a revision of his time) for 10 months after the second surgery. However, initial diagnosis from ICC to CoCC. the follow-up CT revealed a 15-mm hypervascular tumor in the left lateral superior segment (S2), which was com- Discussion patible with a recurrence. As a result, he was then referred CoCC shows a variable histological morphology depend- to another hospital for percutaneous RFA. Abdominal ing on the extent of the associated ICC/HCC compo- ultrasound at the referral hospital showed another 6-mm nents. Such an inherent histological heterogeneity tumor in the remnant segment 4. Both lesions were potentially complicates the pathologic diagnosis of successfully treated by ultrasonography-guided percutan- CoCC. Komuta et al. proposed that CoCC is defined as eous RFA (Cool-Tips; RF Ablation System, Covidien, when the proportion of CoCC accounts for more than Boulder, CO) with a sufficient safety margin. Following 90% of the entire tumor [8]. According to this strict def- the procedure, he underwent gadoxetic acid-enhanced inition, CoCC with a significant proportion of ICC or magnetic resonance imaging (EOB-MRI) every 1 to HCC components may be considered to be an ordinary Fig. 3 Computed tomography images of the initial recurrent lesions. Three well-enhanced masses in segment 4 are observed (arrow). UP umbilical portion of the left portal vein Shinohara et al. Surgical Case Reports (2017) 3:120 Page 4 of 6 Fig. 4 Computed tomography images of a recurrent lesion treated with radio frequency ablation. a A peripherally well-enhanced tumor is seen in segment 3 (arrow). b The index tumor is completely ablated with radio frequency ablation ICC or HCC, respectively [4]. The authors also reported relapse at the positive surgical margin. These results immunohistochemical findings of a positive EMA at the were due to the less aggressive nature of CoCC com- apical membrane [6, 8, 9], positive NCAM (a marker of pared to ICC [4, 6] and partly because of its overlapping hepatic progenitor cells), and negative S100P (a marker nature with HCC. Another related factor was the aggres- of intrahepatic large bile ducts) [8]. As described, we sive strategy employed for this patient’s treatment. We made an incorrect initial diagnosis of ordinary ICC in performed a hepatectomy for the first hepatic recurrence the present patient, primarily because a lack of know- with three tumors and adjuvant chemotherapy using ledge of CoCC led us not to consider the possibility of gemcitabine according to the typical strategy for recur- CoCC. There may be a concern that pathological diag- rent ICC [10]. However, a subsequent liver recurrence nosis of the recurrent lesions treated with RFA was not was found immediately after completion of the planned made. Therefore, de novo HCC cannot be absolutely chemotherapy. This fact suggests that systemic chemo- ruled out. However, recurrence with a short interval and therapy may be not effective for CoCC due to its differ- no underlying liver disease (chronic hepatitis and fatty ent cell lineage. liver) highly suggest CoCC, rather than de novo HCC. To our knowledge, besides the present case, there are The present patient has survived for 9.2 years without three English case reports discussing local treatment for disease despite eight hepatic recurrences and tumor ex- intrahepatic recurrence of CoCC (Table 2) [11–13]. The posure during the second hepatectomy. This favorable initial disease-free intervals ranged from 7 months to outcome was explained by a liver-limited relapse, small 3 years. One patient died of disease 13 months after sur- number and size of the recurrent tumors, and no local gery [11], another patient underwent hepatectomy and Table 1 Intrahepatic recurrence details Recurrence event Interval after primary Recurrence site (size) Treatment Serum CA 19-9 Serum CEA hepatectomy (months) level (U/ml) level (ng/ml) 1 12 S4 (8 mm), S4 partial 32 2.8 S4 (9 mm), resection S4 (26 mm) 2 22 S2 (15 mm), RFA 25 2.9 S4 (6 mm) 3 26 S2 (22 mm) RFA 29 2.9 4 34 S1 (16 mm), RFA 35 3.4 S3 (10 mm) 5 36 S1 (10 mm) RFA 29 2.7 6 41 S3 (7 mm), RFA 29 3.6 S3 (7 mm) 7 43 S3 (10 mm) RFA 26 2.9 8 55 S2 (12 mm) RFA 32 3.8 RFA radiofrequency ablation, CA 19-9 carbohydrate antigen 19-9, CEA carcinoembryonic antigen Shinohara et al. Surgical Case Reports (2017) 3:120 Page 5 of 6 Fig. 5 Histological findings of the recurrent lesion. a Small gland-forming cells proliferate in an anastomosing pattern with abundant fibrous stroma (HE staining, ×200). b The tumor cells (T) proliferate as they replace the noncancerous liver parenchyma (N) without tumor capsule (arrow) (HE staining, ×100). c–g Immunohistochemical studies show that the tumor cells are positive for cytokeratin (CK) 7 and CK19 and negative for neural cell adhesion (NCAM), HepPar1, and S100P. h Epithelial membrane antigen (EMA) stain shows positivity at the apical membranous areas of the ducts survived for 4 years without recurrence [12], and the has been controversial. Transcatheter arterial chemoem- other patient underwent six sessions of hepatectomy bolization (TACE) is another potential option for unre- and survived for 7 years [13]. The present patient under- sectable ICC [18]. The tumor in the present patient went hepatectomy and seven percutaneous RFAs and exhibited enhancement in the arterial phase, which per- has survived for more than 8 years despite several recur- sisted until delayed phase. This CT finding indicates less rences. These findings strongly suggest that localized much cellularity with fibrosis and precludes an efficient treatment may be a promising approach for achieving local control by TACE. Therefore, we performed RFA long-term survival. for the treatment of recurrent ICC, although our first- RFA is a widely applicable treatment for hepatic malig- line approach is surgical resection when technically feas- nancies [14], particularly in unresectable carcinomas. A ible. Further, systemic chemotherapy may be considered few studies and one meta-analysis demonstrated the use- when the recurrent lesion is not amenable to these local fulness of RFA for ICC [15–17]. A large multi- treatments. institutional study, however, failed to show the benefit of Some factors led to successful RFA in the current pa- local treatments compared to systematic chemotherapy; tient. First, CoCC presented as a hepatic parenchymal the median survival times were 18.0 and 16.8 months, mass without periductal and vascular invasions [6]. respectively [18]. Therefore, RFA for unresectable ICC These longitudinal growth patterns [19], if present, are Table 2 Reported cases of cholangiolocellular carcinoma with intrahepatic recurrences controlled by local treatment Reference Age (years), sex Size of primary Interval of initial No. of disease recurrence Treatment for Follow-up tumor (cm) recurrence (months) recurrences (month) Maeda et al. [11] 68, M 3 7 1 1 hepatectomy 13, DOD Yamamoto et al. [12] 61, F Not available 36 1 1 hepatectomy 48, NED Tomioku et al. [13] 59, F 10 18 6 6 hepatectomies 84, NED Present case 40, M 13 10 8 1 hepatectomy 110, NED and 7 RFAs F female, M male, RFA radiofrequency ablation, NED no evidence of disease, DOD died of disease after resection for primary lesion Shinohara et al. Surgical Case Reports (2017) 3:120 Page 6 of 6 not amenable to RFA. Second, intensive follow-up using 2. Hirohashi S, Ishak K, Kojiro M, Wanless I, Theise ND, Tsukuma H, et al. Tumours of the liver and intrahepatic bile ducts. In: Hamilton SR, Aaltonen MRI every 1 to 2 months enabled early detection of liver LA, editors. Pathology and genetics of tumours of the digestive system. recurrences that were small in size and of a limited Lyon: International Agency for Research on Cancer; 2000. p. 157–202. number, as shown in Table 1. Early detection is very im- 3. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, et al. The canals of Hering and hepatic stem cells in humans. Hepatology. 1999;30: portant for RFA because large and multiple tumors are 1425–33. associated with poor prognosis [14]. Meanwhile, such in- 4. Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, et al. tensive follow-up has a disadvantage in terms of cost Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology. 2008;47:1544–56. and time effectiveness. To the best of our knowledge, 5. Theise ND, Nakashima O, Park YN, Nakanuma Y. Combined hepatocellular this is the first study to demonstrate a satisfactory out- cholangiocarcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, come for CoCC after RFA. RFA may be a useful option editors. WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer; 2010. p. 225–7. for limited hepatic recurrences in CoCC. 6. Ariizumi S, Kotera Y, Katagiri S, Nakano M, Nakanuma Y, Saito A, et al. Long- term survival of patients with cholangiolocellular carcinoma after curative hepatectomy. Ann Surg Oncol. 2014;21:451–8. Conclusions 7. Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging manual (7th ed). This case report demonstrated the effectiveness of local- New York: Springer; 2010. ized treatment for hepatic recurrences and a difficult 8. Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, et al. Histological diversity in cholangiocellular carcinoma reflects CoCC diagnosis. Due to the less aggressive nature of the different cholangiocyte phenotypes. Hepatology. 2012;55:1876–88. CoCC, liver-targeting localized therapies benefit patients 9. Nakano M. Histopathological characteristic of cholangiolocellular carcinoma. with liver recurrences of CoCC. RFA can be considered Tan To Sui (Biliary Tract and Pancreas). 2004;25:343–9. (in Japanese) 10. Dingle BH, Rumble RB, Brouwers MC, Group CCOsPiE-BCsGCDS. The role of to be a therapeutic option for limited hepatic recurrence gemcitabine in the treatment of cholangiocarcinoma and gallbladder of CoCC. cancer: a systematic review. Can J Gastroenterol. 2005;19:711–6. 11. Maeda T, Hashimoto K, Ishida T, Yamashita Y, Saeki H, Kawanaka H, et al. Abbreviations Repeat hepatectomy for intrahepatic recurrence of cholangiolocellular AFP: Alpha-fetoprotein; CA19-9: Carbohydrate antigen 19-9; carcinoma. Fukuoka Igaku Zasshi. 2013;104:564–8. CoCC: Cholangiolocellular carcinoma; CT: Computed tomography; 12. Yamamoto M, Takasaki K, Nakano M, Saito A. Hepatic recurrence of EMA: Epithelial membrane antigen; EOB-MRI: Gadoxetic acid-enhanced cholangiolocellular carcinoma: report of a case. Hepato-Gastroenterology. magnetic resonance imaging; HCC: Hepatocellular carcinoma; 1996;43:1046–50. ICC: Intrahepatic cholangiocarcinoma; MRI: Magnetic resonance imaging; 13. Tomioku M, Yazawa N, Furukawa D, Izumi H, Mashiko T, Ozawa S, et al. NCAM: Neural cell adhesion molecule; PIVKA-II: Protein induced by vitamin Repeated hepatectomy for recurrent intrahepatic cholangiolocellular K absence or antagonist-II; RFA: Radiofrequency ablation; TACE: Transcatheter carcinoma: report of a case. Tokai J Exp Clin Med. 2016;41:92–6. arterial chemoembolization 14. Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and Authors’ contributions prognostic factors. Am J Gastroenterol. 2012;107:569–77. KS and TE drafted the manuscript. YS carried out the pathological analysis. 15. Fu Y, Yang W, Wu W, Yan K, Xing BC, Chen MH. Radiofrequency ablation in SS, RY, and TA were involved in the treatment. YY, TI, GS, TM, JY, SS, and MN the management of unresectable intrahepatic cholangiocarcinoma. J Vasc performed the critical revisions of the manuscript. All authors read and Interv Radiol. 2012;23:642–9. approved the final manuscript. 16. Kim JH, Won HJ, Shin YM, Kim KA, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Consent for publication Roentgenol. 2011;196:205–9. Written informed consent was obtained from the patient for the publication 17. Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation of this report and any accompanying images. in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol. 2015;26:943–8. Competing interests 18. Spolverato G, Kim Y, Alexandrescu S, Marques HP, Lamelas J, Aldrighetti L, The authors declare that they have no competing interests. et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Ann Surg Oncol. 2016;23:235–43. Publisher’sNote 19. Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and Springer Nature remains neutral with regard to jurisdictional claims in published molecular pathology of intrahepatic cholangiocarcinoma. J Hepato-Biliary- maps and institutional affiliations. Pancreat Surg. 2003;10:265–81. Author details Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan. Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Department of Gastroenterology, Toshiba General Hospital, Tokyo, Japan. Received: 8 March 2017 Accepted: 9 November 2017 References 1. Steiner PE, Higginson J. Cholangiolocellular carcinoma of the liver. Cancer. 1959;12:753–9. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Surgical Case Reports Springer Journals

Successful local treatment for repeated hepatic recurrences of cholangiolocellular carcinoma: a report on a long-term survivor

Download PDF
6 pages

Loading next page...
1
 
/lp/springer_journal/successful-local-treatment-for-repeated-hepatic-recurrences-of-aKs3am4N4Y

References (23)

Publisher
Springer Journals
Copyright
Copyright © 2017 by The Author(s).
Subject
Medicine & Public Health; Surgery
eISSN
2198-7793
DOI
10.1186/s40792-017-0391-2
Publisher site
See Article on Publisher Site

Abstract

Background: Cholangiolocellular carcinoma (CoCC) is a rare liver tumor arising from the canals of Hering found between the cholangioles and interlobular bile ducts. Although morphologically CoCC mimics intrahepatic cholangiocarcinoma (ICC), CoCC exhibits a unique intermediate biologic behavior between hepatocellular carcinoma (HCC) and ICC. Curative resection is required for prolonged survival in patients with CoCC. However, effective therapy for postoperative hepatic recurrence has not yet been standardized. Case presentation: A 40-year-old man had an asymptomatic liver mass found during a regular medical examination. Contrast-enhanced computed tomography revealed a well-enhanced mass, 15 cm in diameter, in the right liver. He underwent right hemihepatectomy at a local hospital under the preoperative diagnosis of hepatocellular carcinoma. Pathologic examination confirmed a moderately differentiated tubular adenocarcinoma, leading to a diagnosis of ordinary ICC. Twelve months after surgery, he was referred to our hospital due to three hepatic recurrences in the left medial segment. He underwent partial hepatectomy for the recurrence, followed by adjuvant chemotherapy using gemcitabine alone. After the second hepatectomy, hepatic recurrences developed an additional seven times. The numbers and sizes of the recurrent tumors were very limited at each recurrence, satisfying the standard criteria for percutaneous radiofrequency ablation (RFA) for the treatment of HCC. All lesions were treated by percutaneous RFA, although this was an exceptional approach for ICC. He is now alive without evidence of disease 9.2 years after the first hepatectomy. Because his clinical outcome was satisfactory and not compatible with the typical negative outcomes of ordinary ICC, we re-reviewed the histological findings of his tumor. The tumor was composed of small gland-forming cells proliferating in an anastomosing pattern; the cell membrane was strongly immunoreactive for epithelial membrane antigen. These findings were in accordance with the typical features of CoCC, revising his final diagnosis from ICC to CoCC. Conclusions: This case report demonstrates a satisfactory outcome using repeated local treatments, such as hepatectomy and RFA, for hepatic recurrences of CoCC, suggesting that a localized treatment approach can be considered to be a therapeutic option. We should be careful in making a definitive diagnosis of ICC and ruling out CoCC because the diagnosis potentially dictates the treatment strategy for recurrences. Keywords: Radiofrequency ablation, Intrahepatic recurrence, Intrahepatic cholangiocarcinoma, Cholangiolocellular carcinoma * Correspondence: nagino@med.nagoya-u.ac.jp Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Shinohara et al. Surgical Case Reports (2017) 3:120 Page 2 of 6 Background history of chronic hepatitis or fatty liver. Serum tumor Cholangiolocellular carcinoma (CoCC) is a rare primary markers were increased; the patient’s protein induced by liver tumor and was first described by Steiner et al. in vitamin K absence or antagonist-II (PIVKA-II) level was 1959 [1]. This tumor is histologically characterized by 2737 mAU/ml, and his alpha-fetoprotein (AFP) level was small gland-forming tumor cells with variable extents of 23,054 ng/ml. The patient’s serum carbohydrate antigen fibrous stroma. The morphologic features of CoCC resem- 19-9 (CA19-9) level was not measured. Contrast- ble those of the canals of Hering, intervening between the enhanced CT revealed a well-enhanced mass, 15 cm in cholangioles and interlobular bile ducts. However, until re- diameter, in the right liver without extrahepatic lesion cently, this disease had been categorized as a variant of or- (Fig. 1). He underwent right hemihepatectomy without dinary intrahepatic cholangiocarcinoma (ICC) [2]. Theise lymph node dissection under the preoperative diagnosis of et al. observed that the canals of Hering potentially di- HCC (Fig. 2). Histologically, a moderately differentiated verge to hepatocytes and cholangiocytes [3]. Thus, CoCC tubular adenocarcinoma was found, leading to a patho- has an intermediate tumor biology between hepatocellular logic diagnosis of ICC. According to the American Joint carcinoma (HCC) and ICC [4] and is considered to be an Committee on Cancer (7th edition) [7], this tumor was independent disease [5]. classified as pT1NXM0 and R0 resection was achieved. It is well known that CoCC has favorable survival out- An abdominal CT performed 12 months after surgery comes after curative resection [6]. However, because of revealed three hyper vascular tumors in the left medial the rarity of CoCC, clinical outcomes in patients who re- segment (S4), the size of which ranged from 8 to 26 mm lapse remain poorly understood. Herein, we describe a (Fig. 3). He was referred to our hospital, and a partial long-term survivor who had frequent recurrences of hepatectomy of S4 was performed. The liver transection CoCC that were treated by hepatectomy and radiofre- margin was positive (R1 resection) because one tumor quency ablation (RFA). This is the first report showing was adjacent to the umbilical portion of the left the potential utility of RFA for recurrent CoCC. portal vein. The operation time was 337 min, and the blood loss was 637 ml. He had a satisfactory postop- Case presentation erative course and was discharged on postoperative A 40-year-old Japanese man presented to a local hospital day 14. Pathologically, the recurrent tumors were for evaluation of an asymptomatic liver mass detected similar to the primary lesion, leading to a diagnosis of during a regular medical examination. He had no medical recurrent ICC. Fig. 1 Computed tomography images. a Arterial-phase scan shows a peripherally well-enhanced tumor in the right liver (arrow) with vessel penetration (arrow head). Retention of the contrast media in the lesion is observed b from portal phase c to delayed phase Shinohara et al. Surgical Case Reports (2017) 3:120 Page 3 of 6 2 months for surveillance. In total, he developed hepatic recurrences an additional seven times following the sec- ond hepatectomy, and a total of 10 recurrent tumors in all were treated by percutaneous RFA (Fig. 4; Table 1). He is now alive without evidence of disease 9.2 years after the first hepatectomy and 4.7 years after the last RFA. Because his clinical course was not compatible with the usual negative course observed in patients with post- operative liver metastasis of ordinary ICC, we re- reviewed the histological findings of the initial recurrent lesions. The histological slides of the primary tumor were not available. Surprisingly, several specific features of CoCC were found: small-sized gland formation, pro- liferation in an anastomosing pattern, gradual transition to naive hepatocytes, and no mucin production (Fig. 4), while the portal vein area was not found within the tumor. The tumor contained neither ICC-like nor HCC-like areas. Immunohistochemically, the tumor cells Fig. 2 Gross finding of the primary lesion. Cut surface of the tumor were positive for cytokeratin 7 and 19 and negative for shows a yellowish nodule 13 cm in diameter neural cell adhesion molecule (NCAM), HepPar1, and S100P. Epithelial membrane antigen (EMA) was strongly The patient received adjuvant chemotherapy with gem- positive at the apical membrane of the tumor cells citabine alone (the sole regimen for biliary tract cancer (Fig. 5). All these findings, except for negative immuno- that the Japanese national insurance system allowed at the reaction of NCAM, strongly supported a revision of his time) for 10 months after the second surgery. However, initial diagnosis from ICC to CoCC. the follow-up CT revealed a 15-mm hypervascular tumor in the left lateral superior segment (S2), which was com- Discussion patible with a recurrence. As a result, he was then referred CoCC shows a variable histological morphology depend- to another hospital for percutaneous RFA. Abdominal ing on the extent of the associated ICC/HCC compo- ultrasound at the referral hospital showed another 6-mm nents. Such an inherent histological heterogeneity tumor in the remnant segment 4. Both lesions were potentially complicates the pathologic diagnosis of successfully treated by ultrasonography-guided percutan- CoCC. Komuta et al. proposed that CoCC is defined as eous RFA (Cool-Tips; RF Ablation System, Covidien, when the proportion of CoCC accounts for more than Boulder, CO) with a sufficient safety margin. Following 90% of the entire tumor [8]. According to this strict def- the procedure, he underwent gadoxetic acid-enhanced inition, CoCC with a significant proportion of ICC or magnetic resonance imaging (EOB-MRI) every 1 to HCC components may be considered to be an ordinary Fig. 3 Computed tomography images of the initial recurrent lesions. Three well-enhanced masses in segment 4 are observed (arrow). UP umbilical portion of the left portal vein Shinohara et al. Surgical Case Reports (2017) 3:120 Page 4 of 6 Fig. 4 Computed tomography images of a recurrent lesion treated with radio frequency ablation. a A peripherally well-enhanced tumor is seen in segment 3 (arrow). b The index tumor is completely ablated with radio frequency ablation ICC or HCC, respectively [4]. The authors also reported relapse at the positive surgical margin. These results immunohistochemical findings of a positive EMA at the were due to the less aggressive nature of CoCC com- apical membrane [6, 8, 9], positive NCAM (a marker of pared to ICC [4, 6] and partly because of its overlapping hepatic progenitor cells), and negative S100P (a marker nature with HCC. Another related factor was the aggres- of intrahepatic large bile ducts) [8]. As described, we sive strategy employed for this patient’s treatment. We made an incorrect initial diagnosis of ordinary ICC in performed a hepatectomy for the first hepatic recurrence the present patient, primarily because a lack of know- with three tumors and adjuvant chemotherapy using ledge of CoCC led us not to consider the possibility of gemcitabine according to the typical strategy for recur- CoCC. There may be a concern that pathological diag- rent ICC [10]. However, a subsequent liver recurrence nosis of the recurrent lesions treated with RFA was not was found immediately after completion of the planned made. Therefore, de novo HCC cannot be absolutely chemotherapy. This fact suggests that systemic chemo- ruled out. However, recurrence with a short interval and therapy may be not effective for CoCC due to its differ- no underlying liver disease (chronic hepatitis and fatty ent cell lineage. liver) highly suggest CoCC, rather than de novo HCC. To our knowledge, besides the present case, there are The present patient has survived for 9.2 years without three English case reports discussing local treatment for disease despite eight hepatic recurrences and tumor ex- intrahepatic recurrence of CoCC (Table 2) [11–13]. The posure during the second hepatectomy. This favorable initial disease-free intervals ranged from 7 months to outcome was explained by a liver-limited relapse, small 3 years. One patient died of disease 13 months after sur- number and size of the recurrent tumors, and no local gery [11], another patient underwent hepatectomy and Table 1 Intrahepatic recurrence details Recurrence event Interval after primary Recurrence site (size) Treatment Serum CA 19-9 Serum CEA hepatectomy (months) level (U/ml) level (ng/ml) 1 12 S4 (8 mm), S4 partial 32 2.8 S4 (9 mm), resection S4 (26 mm) 2 22 S2 (15 mm), RFA 25 2.9 S4 (6 mm) 3 26 S2 (22 mm) RFA 29 2.9 4 34 S1 (16 mm), RFA 35 3.4 S3 (10 mm) 5 36 S1 (10 mm) RFA 29 2.7 6 41 S3 (7 mm), RFA 29 3.6 S3 (7 mm) 7 43 S3 (10 mm) RFA 26 2.9 8 55 S2 (12 mm) RFA 32 3.8 RFA radiofrequency ablation, CA 19-9 carbohydrate antigen 19-9, CEA carcinoembryonic antigen Shinohara et al. Surgical Case Reports (2017) 3:120 Page 5 of 6 Fig. 5 Histological findings of the recurrent lesion. a Small gland-forming cells proliferate in an anastomosing pattern with abundant fibrous stroma (HE staining, ×200). b The tumor cells (T) proliferate as they replace the noncancerous liver parenchyma (N) without tumor capsule (arrow) (HE staining, ×100). c–g Immunohistochemical studies show that the tumor cells are positive for cytokeratin (CK) 7 and CK19 and negative for neural cell adhesion (NCAM), HepPar1, and S100P. h Epithelial membrane antigen (EMA) stain shows positivity at the apical membranous areas of the ducts survived for 4 years without recurrence [12], and the has been controversial. Transcatheter arterial chemoem- other patient underwent six sessions of hepatectomy bolization (TACE) is another potential option for unre- and survived for 7 years [13]. The present patient under- sectable ICC [18]. The tumor in the present patient went hepatectomy and seven percutaneous RFAs and exhibited enhancement in the arterial phase, which per- has survived for more than 8 years despite several recur- sisted until delayed phase. This CT finding indicates less rences. These findings strongly suggest that localized much cellularity with fibrosis and precludes an efficient treatment may be a promising approach for achieving local control by TACE. Therefore, we performed RFA long-term survival. for the treatment of recurrent ICC, although our first- RFA is a widely applicable treatment for hepatic malig- line approach is surgical resection when technically feas- nancies [14], particularly in unresectable carcinomas. A ible. Further, systemic chemotherapy may be considered few studies and one meta-analysis demonstrated the use- when the recurrent lesion is not amenable to these local fulness of RFA for ICC [15–17]. A large multi- treatments. institutional study, however, failed to show the benefit of Some factors led to successful RFA in the current pa- local treatments compared to systematic chemotherapy; tient. First, CoCC presented as a hepatic parenchymal the median survival times were 18.0 and 16.8 months, mass without periductal and vascular invasions [6]. respectively [18]. Therefore, RFA for unresectable ICC These longitudinal growth patterns [19], if present, are Table 2 Reported cases of cholangiolocellular carcinoma with intrahepatic recurrences controlled by local treatment Reference Age (years), sex Size of primary Interval of initial No. of disease recurrence Treatment for Follow-up tumor (cm) recurrence (months) recurrences (month) Maeda et al. [11] 68, M 3 7 1 1 hepatectomy 13, DOD Yamamoto et al. [12] 61, F Not available 36 1 1 hepatectomy 48, NED Tomioku et al. [13] 59, F 10 18 6 6 hepatectomies 84, NED Present case 40, M 13 10 8 1 hepatectomy 110, NED and 7 RFAs F female, M male, RFA radiofrequency ablation, NED no evidence of disease, DOD died of disease after resection for primary lesion Shinohara et al. Surgical Case Reports (2017) 3:120 Page 6 of 6 not amenable to RFA. Second, intensive follow-up using 2. Hirohashi S, Ishak K, Kojiro M, Wanless I, Theise ND, Tsukuma H, et al. Tumours of the liver and intrahepatic bile ducts. In: Hamilton SR, Aaltonen MRI every 1 to 2 months enabled early detection of liver LA, editors. Pathology and genetics of tumours of the digestive system. recurrences that were small in size and of a limited Lyon: International Agency for Research on Cancer; 2000. p. 157–202. number, as shown in Table 1. Early detection is very im- 3. Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, et al. The canals of Hering and hepatic stem cells in humans. Hepatology. 1999;30: portant for RFA because large and multiple tumors are 1425–33. associated with poor prognosis [14]. Meanwhile, such in- 4. Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, et al. tensive follow-up has a disadvantage in terms of cost Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology. 2008;47:1544–56. and time effectiveness. To the best of our knowledge, 5. Theise ND, Nakashima O, Park YN, Nakanuma Y. Combined hepatocellular this is the first study to demonstrate a satisfactory out- cholangiocarcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, come for CoCC after RFA. RFA may be a useful option editors. WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer; 2010. p. 225–7. for limited hepatic recurrences in CoCC. 6. Ariizumi S, Kotera Y, Katagiri S, Nakano M, Nakanuma Y, Saito A, et al. Long- term survival of patients with cholangiolocellular carcinoma after curative hepatectomy. Ann Surg Oncol. 2014;21:451–8. Conclusions 7. Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging manual (7th ed). This case report demonstrated the effectiveness of local- New York: Springer; 2010. ized treatment for hepatic recurrences and a difficult 8. Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W, Verslype C, et al. Histological diversity in cholangiocellular carcinoma reflects CoCC diagnosis. Due to the less aggressive nature of the different cholangiocyte phenotypes. Hepatology. 2012;55:1876–88. CoCC, liver-targeting localized therapies benefit patients 9. Nakano M. Histopathological characteristic of cholangiolocellular carcinoma. with liver recurrences of CoCC. RFA can be considered Tan To Sui (Biliary Tract and Pancreas). 2004;25:343–9. (in Japanese) 10. Dingle BH, Rumble RB, Brouwers MC, Group CCOsPiE-BCsGCDS. The role of to be a therapeutic option for limited hepatic recurrence gemcitabine in the treatment of cholangiocarcinoma and gallbladder of CoCC. cancer: a systematic review. Can J Gastroenterol. 2005;19:711–6. 11. Maeda T, Hashimoto K, Ishida T, Yamashita Y, Saeki H, Kawanaka H, et al. Abbreviations Repeat hepatectomy for intrahepatic recurrence of cholangiolocellular AFP: Alpha-fetoprotein; CA19-9: Carbohydrate antigen 19-9; carcinoma. Fukuoka Igaku Zasshi. 2013;104:564–8. CoCC: Cholangiolocellular carcinoma; CT: Computed tomography; 12. Yamamoto M, Takasaki K, Nakano M, Saito A. Hepatic recurrence of EMA: Epithelial membrane antigen; EOB-MRI: Gadoxetic acid-enhanced cholangiolocellular carcinoma: report of a case. Hepato-Gastroenterology. magnetic resonance imaging; HCC: Hepatocellular carcinoma; 1996;43:1046–50. ICC: Intrahepatic cholangiocarcinoma; MRI: Magnetic resonance imaging; 13. Tomioku M, Yazawa N, Furukawa D, Izumi H, Mashiko T, Ozawa S, et al. NCAM: Neural cell adhesion molecule; PIVKA-II: Protein induced by vitamin Repeated hepatectomy for recurrent intrahepatic cholangiolocellular K absence or antagonist-II; RFA: Radiofrequency ablation; TACE: Transcatheter carcinoma: report of a case. Tokai J Exp Clin Med. 2016;41:92–6. arterial chemoembolization 14. Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Nakagawa H, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and Authors’ contributions prognostic factors. Am J Gastroenterol. 2012;107:569–77. KS and TE drafted the manuscript. YS carried out the pathological analysis. 15. Fu Y, Yang W, Wu W, Yan K, Xing BC, Chen MH. Radiofrequency ablation in SS, RY, and TA were involved in the treatment. YY, TI, GS, TM, JY, SS, and MN the management of unresectable intrahepatic cholangiocarcinoma. J Vasc performed the critical revisions of the manuscript. All authors read and Interv Radiol. 2012;23:642–9. approved the final manuscript. 16. Kim JH, Won HJ, Shin YM, Kim KA, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Consent for publication Roentgenol. 2011;196:205–9. Written informed consent was obtained from the patient for the publication 17. Han K, Ko HK, Kim KW, Won HJ, Shin YM, Kim PN. Radiofrequency ablation of this report and any accompanying images. in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol. 2015;26:943–8. Competing interests 18. Spolverato G, Kim Y, Alexandrescu S, Marques HP, Lamelas J, Aldrighetti L, The authors declare that they have no competing interests. et al. Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection. Ann Surg Oncol. 2016;23:235–43. Publisher’sNote 19. Nakanuma Y, Harada K, Ishikawa A, Zen Y, Sasaki M. Anatomic and Springer Nature remains neutral with regard to jurisdictional claims in published molecular pathology of intrahepatic cholangiocarcinoma. J Hepato-Biliary- maps and institutional affiliations. Pancreat Surg. 2003;10:265–81. Author details Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Department of Pathology and Clinical Laboratories, Nagoya University Graduate School of Medicine, Nagoya, Japan. Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Department of Gastroenterology, Toshiba General Hospital, Tokyo, Japan. Received: 8 March 2017 Accepted: 9 November 2017 References 1. Steiner PE, Higginson J. Cholangiolocellular carcinoma of the liver. Cancer. 1959;12:753–9.

Journal

Surgical Case Reports – Springer Journals

Published: Dec 2, 2017

There are no references for this article.