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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 53  |  Issue : 6  |  Page : 236-239

Double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma


1 Division of General Surgery, Department of Surgery, Cardinal Tien Hospital; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
2 School of Medicine, College of Medicine, Fu Jen Catholic University; Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, New Taipei City, Taiwan

Date of Submission21-Apr-2020
Date of Decision05-May-2020
Date of Acceptance14-Jul-2020
Date of Web Publication19-Dec-2020

Correspondence Address:
Yi-Hsuan Hu
Division of Surgery, Department of Surgery, Cardinal Tien Hospital, No. 362, Zhongzheng Rd., Xindian Dist., New Taipei City 23155
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_54_20

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  Abstract 


We report a patient with double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma (dpHCC-ICC) who received surgical intervention at our institute. The incidence of dpHCC-ICC is extremely low. To the best of our knowledge, only 134 of these cases have been reported in the English literature worldwide.

Keywords: Cholangiocarcinoma, double cancer, hepatocellular carcinoma


How to cite this article:
Hu YH, Hou YC. Double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Formos J Surg 2020;53:236-9

How to cite this URL:
Hu YH, Hou YC. Double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Formos J Surg [serial online] 2020 [cited 2021 Jan 23];53:236-9. Available from: https://www.e-fjs.org/text.asp?2020/53/6/236/304022




  Introduction Top


The simultaneous development of primary hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in two independent locations of the liver is extremely rare. This condition is also known as double primary HCC-ICC (dpHCC-ICC). The incidence of dpHCC-ICC is very low, and only 134 of these cases have been reported in the English literature worldwide.[1],[2]


  Case Report Top


A 54-year-old male had been followed up regularly at our family medicine clinic because of chronic hepatitis B. As an alcoholic and smoker, he had no obvious abdominal discomfort during the check-up examinations, and his baseline liver function and hepatitis B viral DNA titer were within the normal limits. A recent abdominal sonography revealed that a hypoechoic liver tumor in the left lobe.

Further imaging studies, including dynamic contrast-enhanced abdominal computed tomography (CT) and magnetic resonance imaging (MRI), showed three hepatic lesions: Two located at S2 and one located at S4 (which was the largest and with a size of 2.5 cm × 2.3 cm × 1.8 cm). On CT, the lesions showed early enhancement in the arterial phase and early washout during the delayed postcontrast phase [Figure 1]. On MRI, the lesions were hyperintense on T2-weighted imaging and hypointense on T1-weighted imaging. Multifocal HCC was first considered. Tumor marker studies, including alpha-fetoprotein (AFP), carcinoembryonic antigen, CA-199 all showed normal findings.
Figure 1: The preoperative contrast-enhanced computed tomography showed three hepatic nodular lesions at S2 and S4 (marked A, B, and C). The lesions presented with contrast enhancement patterns typical of hepatocellular carcinoma

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After the preoperative workup, we performed open S2, S3, and S4a liver segmentectomy for this patient. During surgical exploration, no hilar lymphadenopathy or peritoneal seeding was observed. The intraoperative sonography showed no other notable lesions, and the liver was healthy without cirrhotic changes. On inspection of the resected specimen, three well-demarcated whitish tumors were observed; these tumors were indistinguishable from each other on gross appearance [Figure 2]a and [Figure 2]b. The postoperative recovery process was smooth without immediate complications.
Figure 2: The resected gross specimen showed three well-demarcated whitish tumors, and the markings A, B, and C correspond to the markings shown in Figure 1. (a) The close-up view of the “lesion A”. (b) The close-up view of the “lesion B” and “lesion C”

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The pathology study showed surprising results: the large nodule at S2 (size 2.5 cm × 2.3 cm × 2.0 cm, lesion B) consisted of ICC, histologic Grade 2 [Figure 3]; the small nodule at S2 (size 1.5 cm × 1.2 cm × 1.0 cm, lesion C) and the nodule at S4a (size 3.0 cm × 2.2 cm × 2.2 cm, lesion A) consisted of HCC, histologic Grade 3 [Figure 4]. Immunostaining of the ICC showed positive results for CK7, CK20, and CA199 and negative results for hepatocytes. For the HCC portion, immunostaining showed positive results for hepatocytes and CD34. The resection margins were free of tumor invasion. All three lesions showed an absence of tumor emboli or lymphovascular invasion. The pathological stage of HCC was pT2N0M0, Stage II; the pathology stage of ICC was pT1N0M0, Stage I.
Figure 3: The pathology slide from the “B lesion” revealed glandular structures composed of hyperchromatic and pleomorphic neoplastic epithelial cells, which were compatible with cholangiocarcinoma

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Figure 4: The pathology slides from the “A lesion” and “C lesion” revealed hyperchromatic and pleomorphic neoplastic hepatocytes lined in a trabecular pattern, which was compatible with hepatocellular carcinoma

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The patient then received routine surveillance at our surgical clinic without adjuvant treatment. The abdominal CT obtained 3 months after the operation revealed no intrahepatic recurrence, but lymphadenopathies developed along the celiac axis and paracaval region [Figure 5]. Pathology samples obtained through CT-guided biopsy suggested that these were metastatic HCC lesions. We then arranged concurrent chemotherapy (cisplatin plus gemcitabine) and radiotherapy for the patient (Sorafenib was not chosen due to economic stress). Nine months after the operation, the patient had a good performance status, and the metastatic nodes showed a partial response to current treatment [Figure 6]. However, 16 months after the operation, the patient developed bony metastasis and cancer-related cachexia, he then died of disease progression because this time he opt for palliative management.
Figure 5: Metastatic lymphadenopathies developed in the paracaval region (yellow arrowhead)

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Figure 6: The metastatic lymph node (yellow arrowhead) regressed in size after radiation and chemotherapy

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  Discussion Top


Combined hepatocellular and cholangiocarcinoma accounts for 0.54% to 14.2% of all primary liver cancers.[3],[4],[5] This combination can be subsequently divided into three subtypes according to Allen and Lisa:[6] Type A, separate nodules of HCC and ICC; type B, contiguous masses of HCC and ICC; and type C, individual masses intermingling with components of HCC and ICC. The incidence of type A tumors, which are also considered true dpHCC-ICC, is unknown due to its exceedingly rare nature.[7],[8],[9],[10],[11] Two larger series published in 2016 estimated the incidence of dpHCC-ICC to be far <1%.[1],[2]

The preoperative diagnosis of dpHCC-ICC is difficult because the clinical presentation and imaging features often mimic those of multifocal HCC. Even with the aid of imaging studies and tumor markers, the diagnosis of dpHCC-ICC is often an incidental pathological finding after surgical resection.[2]

Hepatic resection is the primary treatment for all resectable malignant hepatic tumors, but the approach for lymph node dissection differs between HCC and ICC. During hepatic resection for HCC, the only resection of the liver tumor is required because of the low incidence of nodal metastases, while the presence of ICC makes lymph node dissection essential. Under this circumstance, without a preoperative diagnosis of concurrent ICC, we would not perform lymph node dissection, which therefore could lead to the possible understaging of the ICC part of the tumor. This is an important clinical issue because according to previous reports, the prognosis of dpHCC-ICC patients showed more correlation with the ICC stage than that with the HCC stage.[2],[3] To avoid understaging, an intraoperative frozen biopsy may be indicated for lesions not typical for HCC.[9] Unfortunately, because dpHCC-ICC is so rare, a correct diagnosis mostly relies on final pathologic and immunohistochemistry studies.

Immunohistochemistry is the key to a correct diagnosis of dpHCC-ICC. Similar to how Hepa and AFP are reliable markers for HCC,[12] CK7, and CK19 are valuable markers for identifying ICC.[13] In our case, the HCC part showed positive results for Hepa, and the ICC part showed positive results for CK7 and negative results for Hepa.

The prognosis of dpHCC-ICC is less favorable than that of either HCC or ICC due to the high rate of disease recurrence and metastasis;[1],[2],[3] however, there is no standard adjuvant treatment suggestion after dpHCC-ICC resection due to the rarity of this tumor. In the Chinese series conducted by Li et al.,[1] postoperative prophylactic transarterial chemoembolization may have prolonged the disease-free survival of these patients but had no effect on improving overall survival. For our patient, adjuvant treatment was not initially arranged because of the unclear survival benefits. However, during regular surveillance, we quickly discovered that the patient developed metastatic lymphadenopathies along the celiac axis and paracaval regions through abdominal CT scans. The pathology obtained from the enlarged lymph nodes through CT-guided biopsy confirmed the diagnosis of metastatic HCC. This makes our case unique because, according to previous reports, metastatic lesions are typically composed of ICC.[2] When treating the metastatic lymph nodes, in our experience, concurrent chemotherapy (cisplatin plus gemcitabine) and radiotherapy seem to be beneficial for disease control.

In summary, we report an extremely rare case of dpHCC-ICC, with HCC and ICC occurring simultaneously in separate locations within the liver. In such cases, it is difficult to determine the diagnosis preoperatively. The final diagnosis depends on the pathological and immunohistochemical examination results. Hepatic resection remains the primary treatment option. The prognosis of dpHCC-ICC is unfavorable due to the high risk for distant metastasis. Our case is unique because the metastatic lymph node component was composed of HCC instead of ICC. Unfortunately, there is currently no reliable adjuvant treatment to aid these patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Li A, Ma S, Pawlik T, Wu B, Yang X, Cui L, et al. Surgical treatment of double primary liver cancer: An observational study for a rare type of tumor. Medicine (Baltimore) 2016;95: e4412.  Back to cited text no. 1
    
2.
Jung DH, Hwang S, Kim KH, Hong SM, Lee YJ, Ahn CS, et al. Clinicopathological features and post-resection prognosis of double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma. World J Surg 2017;41:825-34.  Back to cited text no. 2
    
3.
Cao J, Huang L, Liu C, Li J, Zhang X, Shen J, et al. Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) in a single patient: A clinicopathologic study of 35 resected cases. J Gastroenterol Hepatol 2013;28:1025-31.  Back to cited text no. 3
    
4.
Koh KC, Lee H, Choi MS, Lee JH, Paik SW, Yoo BC, et al. Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg 2005;189:120-5.  Back to cited text no. 4
    
5.
Kudo M, Izumi N, Ichida T, Ku Y, Kokudo N, Sakamoto M, et al. Report of the 19th follow-up survey of primary liver cancer in Japan. Hepatol Res 2016;46:372-90.  Back to cited text no. 5
    
6.
Allen RA, LISA JR. Combined liver cell and bile duct carcinoma. Am J Pathol 1949;25:647-55.  Back to cited text no. 6
    
7.
Watanabe T, Sakata J, Ishikawa T, Shirai Y, Suda T, Hirono H, et al. Synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type C liver cirrhosis. World J Hepatol 2009;1:103-9.  Back to cited text no. 7
    
8.
Jung KS, Chun KH, Choi GH, Jeon HM, Shin HS, Park YN, et al. Synchronous development of intrahepatic cholangiocarcinoma and hepatocellular carcinoma in different sites of the liver with chronic B-viral hepatitis: Two case reports. BMC Res Notes 2013;6:520.  Back to cited text no. 8
    
9.
Wu C, Bai DS, Jiang GQ, Jin SJ. Synchronous double cancers of primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma: A case report and review of the literature. World J Surg Oncol 2014;12:337.  Back to cited text no. 9
    
10.
Zhou R, Zhang M, Cheng N, Zhou Y. Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) in a single patient: A case report. Oncol Lett 2016;11:273-6.  Back to cited text no. 10
    
11.
Hu J, Yuan R, Huang C, Shao J, Zou S, Wang K. Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) originating from hepatic progenitor cell: A case report and review of the literature. World J Surg Oncol 2016;14:218.  Back to cited text no. 11
    
12.
Jeng KS, Sheen IS, Jeng WJ, Yu MC, Hsiau HI, Chang FY, et al. Activation of the sonic hedgehog signaling pathway occurs in the CD133 positive cells of mouse liver cancer Hepa 1-6 cells. Onco Targets Ther 2013;6:1047-55.  Back to cited text no. 12
    
13.
Massani M, Stecca T, Fabris L, Caratozzolo E, Ruffolo C, Furlanetto A, et al. Isolation and characterization of biliary epithelial and stromal cells from resected human cholangiocarcinoma: A novel in vitro model to study tumor-stroma interactions. Oncol Rep 2013;30:1143-8.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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