Journal of Yeungnam Medical Science

Review articles

Overview of hepatocarcinogenesis focusing on cellular origins of liver cancer stem cells: a narrative review: Jong Ryeol Eun; Received September 22, 2024 Accepted October 2, 2024 Published online November 11, 2024; DOI: https://doi.org/10.12701/jyms.2024.01088 [Epub ahead of print]

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Abstract PDF: Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers and generally has a poor prognosis. The hierarchical model, which posits that HCC originates from liver cancer stem cells (CSCs), is now widely accepted, as it is for other cancer types. As CSCs typically reside in the G0 phase of the cell cycle, they are resistant to conventional chemotherapy. Therefore, to effectively treat HCC, developing therapeutic strategies that target liver CSCs is essential. Clinically, HCCs exhibit a broad spectrum of pathological and clinical characteristics, ranging from well-differentiated to poorly differentiated forms, and from slow-growing tumors to aggressive ones with significant metastatic potential. Some patients with HCC also show features of cholangiocarcinoma. This HCC heterogeneity may arise from the diverse cellular origins of liver CSCs. This review explores the normal physiology of liver regeneration and provides a comprehensive overview of hepatocarcinogenesis, including cancer initiation, isolation of liver CSCs, molecular signaling pathways, and microRNAs. Additionally, the cellular origins of liver CSCs are reviewed, emphasizing hematopoietic and mesenchymal stem cells, along with the well-known hepatocytes and hepatic progenitor cells.

Pathology and diagnostic approaches to well-differentiated hepatocellular lesions: a narrative review: Joon Hyuk Choi, Swan N. Thung; Received July 24, 2024 Accepted September 19, 2024 Published online October 24, 2024; DOI: https://doi.org/10.12701/jyms.2024.00766 [Epub ahead of print]

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Abstract PDF: Well-differentiated hepatocellular lesions (WDHLs) are liver tumors or nonneoplastic lesions in which the cells closely resemble normal hepatocytes. These lesions often include focal nodular hyperplasia, hepatocellular adenoma, macroregenerative nodule, dysplastic nodule, and well-differentiated hepatocellular carcinoma. The diagnosis of these lesions remains challenging because of their morphological similarities, particularly when examined using needle biopsy. The accurate diagnosis of WDHLs is crucial for patient management and prognosis. This review addresses the histopathological characteristics and diagnostic approaches of WDHLs.

Clinical significance of exosomal noncoding RNAs in hepatocellular carcinoma: a narrative review: Jae Sung Yoo, Min Kyu Kang; Received October 30, 2023 Accepted December 30, 2023 Published online February 8, 2024; DOI: https://doi.org/10.12701/jyms.2023.01186 [Epub ahead of print]

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Abstract PDF: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, with poor prognosis owing to its high frequency of recurrence and metastasis. Moreover, most patients are diagnosed at an advanced stage owing to a lack of early detection markers. Exosomes, which are characterized by their cargos of stable intracellular messengers, such as DNA, RNA, proteins, and lipids, play a crucial role in regulating cell differentiation and HCC development. Recently, exosomal noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, and circular RNAs, have become increasingly important diagnostic, prognostic, and predictive markers of HCC. Herein, we discuss the clinical implications of exosomal ncRNAs, specifically those within the HCC regulatory network.

Current status of stereotactic body radiotherapy for the treatment of hepatocellular carcinoma: Jongmoo Park, Jae Won Park, Min Kyu Kang; Yeungnam Univ J Med. 2019;36(3):192-200. Published online August 12, 2019; DOI: https://doi.org/10.12701/yujm.2019.00269

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Stereotactic body radiotherapy (SBRT) is an advanced form of radiotherapy (RT) with a growing interest on its application in the treatment of hepatocellular carcinoma (HCC). It can deliver ablative radiation doses to tumors in a few fractions without excessive doses to normal tissues, with the help of advanced modern RT and imaging technologies. Currently, SBRT is recommended as an alternative to curative treatments, such as surgery and radiofrequency ablation. This review discusses the current status of SBRT to aid in the decision making on how it is incorporated into the HCC management.

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Dosimetric Comparison Study Between Free Breathing and Breath Hold Techniques in Patients Treated by Liver-Directed Stereotactic Body Radiation Therapy
Atsuto Katano, Tomoyuki Noyama, Kosuke Morishima, Yuki Nozawa, Hideomi Yamashita
Cureus.2023;[Epub] CrossRef
The role of stereotactic body radiotherapy (SBRT) in the treatment of recurrent / progressive lung lesions after primary treatment
H. Demir, S. Özdemir, N. Işık, G. Yaprak
International Journal of Radiation Research.2023; 21(4): 727. CrossRef
Gastric Fistula After MR-Guided Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma
Sarah Goodchild, Matthew N. Mills, Russell F. Palm, Sarah E. Hoffe, Jessica M. Frakes
Applied Radiation Oncology.2023; 12(4): 40. CrossRef
MRI features of treated hepatocellular carcinoma following locoregional therapy: a pictorial review
Mohanned Alnammi, Jeremy Wortman, Jaclyn Therrien, Jalil Afnan
Abdominal Radiology.2022; 47(7): 2299. CrossRef
Radiofrequency ablation versus laparoscopic hepatectomy for treatment of hepatocellular carcinoma: a systematic review and meta-analysis
Shan Jin, Shisheng Tan, Wen Peng, Ying Jiang, Chunshan Luo
World Journal of Surgical Oncology.2020;[Epub] CrossRef

Case Reports

Secondary adrenal insufficiency caused by sorafenib administration in a patient with hepatocellular carcinoma.: Soo Yeon Jo, Soo Hyung Ryu, Mi Young Kim, Jeong Seop Moon, Won Jae Yoon, Jin Nam Kim; Yeungnam Univ J Med. 2016;33(2):155-158. Published online December 31, 2016; DOI: https://doi.org/10.12701/yujm.2016.33.2.155

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Abstract PDF: Sorafenib (Nexavar) has been regarded as a treatment for unresectable hepatocellular carcinoma (HCC), with side effects that include hand-foot skin reaction, diarrhea, rash, fatigue, hypertension, nausea, anorexia, weight loss, and alopecia. Thyroid disorder, such as endocrine side effect, has also been reported. However no case involving adrenal insufficiency has been reported. Here, we report a case of adrenal insufficiency which occurred after taking sorafenib in a patient with HCC. A 56-year-old man visited our hospital due to right upper quadrant abdominal pain and he was diagnosed as multiple disseminated and unresectable HCCs with portal vein invasion; therefore transarterial chemoembolization was performed and sorafenib administration was started. Two months later, he was admitted to the hospital complaining of severe fatigue. The laboratory results showed cortisol of <0.2µ g/dL and adrenocorticotropic hormone of <1.00 pg/mL. The patient had no history of taking steroids or herbal medications. Secondary adrenal insufficiency was diagnosed and prednisolone 10 mg per day was started immediately; as a result, fatigue remarkably improved. This may be the first report indicating a possible association between sorafenib and adrenal insufficiency and it implies that the possibility of adrenal insufficiency should be considered in patients taking sorafenib who complain of severe fatigue.

Tumor lysis syndrome following sorafenib treatment in hepatocellular carcinoma.: Shin Young Kim, Hee Yeon Kim, Yu Seung Kim, Sang Min Lee, Chang Wook Kim; Yeungnam Univ J Med. 2015;32(1):47-49. Published online June 30, 2015; DOI: https://doi.org/10.12701/yujm.2015.32.1.47

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Abstract PDF

Sorafenib is indicated for the treatment of advanced hepatocellular carcinoma (HCC), but although rare, tumor lysis syndrome (TLS) can be fatal in HCC patients with a large tumor burden. The authors describe the case of a 55-year-old hepatitis B carrier who visited our clinic with progressive dyspnea for 3 weeks. Chest and abdominal computed tomography revealed a huge HCC in the left lobe of the liver with invasion of the inferior vena cava, right atrium, and pulmonary arteries. After 8 days of sorafenib administration, TLS was diagnosed based on the characteristic findings of hyperuricemia, hyperkalemia, and acute kidney injury with massive tumor necrosis by follow-up imaging. Despite discontinuation of sorafenib and supportive care, the patient's clinical course rapidly deteriorated. The authors describe a rare but fatal complication that occurred soon after sorafenib initiation for HCC. Careful follow-up is required after commencing sorafenib therapy for the early diagnosis and management of TLS.

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A case of hepatocellular carcinoma caused severe tumor lysis by ramucirumab
Yuhi Sakamoto, Keizo Kato, Hiroshi Abe, Takeshi Yonezawa, Sadahiro Ito, Makiko Ika, Kiichiro Yoza, Mamika Ohara, Shogo Sakasai, Shohei Shimizu, Shinji Endo
Kanzo.2021; 62(3): 129. CrossRef
Sorafenib-induced tumor lysis syndrome in a patient with metastatic hepatocellular carcinoma
Sardar Zakariya Imam, Mohammad Faizan Zahid, Muhammad Asad Maqbool
Hematology/Oncology and Stem Cell Therapy.2020; 13(3): 168. CrossRef

Review

Cellular origin of liver cancer stem cells.: Jong Ryeol Eun; Yeungnam Univ J Med. 2015;32(1):1-7. Published online June 30, 2015; DOI: https://doi.org/10.12701/yujm.2015.32.1.1

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Abstract PDF: Over several decades, a hierarchical cancer stem cell (CSC) model has been established in development of solid cancers, including hepatocellular carcinoma(HCC). In terms of this concept, HCCs originate from liver CSCs. Clinically HCCs show a wide range of manifestations from slow growth to very aggressive metastasis. One of the reasons may be that liver CSCs originate from different cells. This review describes the basic concept of CSCs and the cellular origin of liver CSCs.

Case Reports

Lipiodol-induced pneumonitis following transarterial chemoembolization for ruptured hepatocellular carcinoma.: Haewon Kim, Yong Hoon Kim, Hong Jin Yoon, Kwang Hoon Lee, Seung Moon Joo, Min Kwang Byun, Jung Il Lee, Kwan Sik Lee, Ja Kyung Kim; Yeungnam Univ J Med. 2014;31(2):117-121. Published online December 31, 2014; DOI: https://doi.org/10.12701/yujm.2014.31.2.117

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Transarterial chemoembolization (TACE) is a widely accepted nonsurgical modality used for the treatment of multinodular hepatocellular carcinoma (HCC). The careful selection of the candidate is important due to the risk of developing various side effects. Fever, nausea, abdominal pain, and liver enzyme elevation are commonly known side effects of TACE. Hepatic failure, ischemic cholecystitis, and cerebral embolism are also reported, although their incidence might be low. Pulmonary complication after TACE is rare, and the reported cases of lipiodol pneumonitis are even rarer. A 53-year-old man was treated with TACE for ruptured HCC associated with hepatitis B virus infection. On day 19 after the procedure, the patient complained of dyspnea and dry cough. Chest computed tomography showed diffuse ground glass opacities in the wholelung fields, suggesting lipiodol-induced pneumonitis. After 2 weeks of conservative management, the clinical symptoms and radiologic abnormalities improved. Reported herein is the aforementioned case of lipiodol-induced pnemonitis after TACE, with literature review.

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Lipiodol Pneumonitis Following Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma
Sungkeun Kim, Hee Yeon Kim, Su Lim Lee, Young Mi Ku, Yoo Dong Won, Chang Wook Kim
Journal of Liver Cancer.2020; 20(1): 60. CrossRef
Secondary adrenal insufficiency caused by sorafenib administration in a patient with hepatocellular carcinoma
Soo Yeon Jo, Soo Hyung Ryu, Mi Young Kim, Jeong Seop Moon, Won Jae Yoon, Jin Nam Kim
Yeungnam University Journal of Medicine.2016; 33(2): 155. CrossRef

A Case of Metastatic Hepatocellular Carcinoma of the Orbit.: Young Joo Yang, Seung Hyeon Bae, Il Young Jang, Mi Jung Jun, Ji Won Jung, Ji Hyun An, Ju Hyun Shim; Yeungnam Univ J Med. 2013;30(2):152-155. Published online December 31, 2013; DOI: https://doi.org/10.12701/yujm.2013.30.2.152

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Abstract PDF: Orbital metastasis from hepatocellular carcinoma is very rare, with only 14 biopsy-proven cases from hepa tocellular carcinoma cases reported in English literature and three cases reported in Korea. Common symptoms of orbital metastasis are proptosis, visual loss, ocular pain and oculomotor dysfunction. For its precise diagnosis, we can perform fine needle aspiration biopsy, orbit CT or MRI, and ultrasonography. Radiotherapy is the mainstay in the treatment of orbital metastasis. In addition, chemotherapy, hormonal therapy and surgical intervention can play a role in the treatment of orbital metastasis according to the primary cancer and symptoms. However, the prognosis of orbital metastasis is poor. We report herein a rare case of a patient with orbital metastasis from hepatocellular carcinoma, which was treated with various modalities that included resection, and who had good clinical and radiological responses to radiation therapy and sorafenib (Nexavar, Bayer HealthCare).

Huge Hepatocellular Carcinoma Abruptly Developed within 3 Months.: Sang Hyuk Lee, Byung Ik Kim, Chang Uk Chon, Ki Bae Bang, Eun Haeng Jeong, Jeong Yeon Seo, Eun Hye Park, Ji Soo Seol; Yeungnam Univ J Med. 2012;29(1):48-53. Published online June 30, 2012; DOI: https://doi.org/10.12701/yujm.2012.29.1.48

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Abstract PDF: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in South Korea. To decrease its mortality rate, its early detection is very important. Screening for HCC detection has been accepted as the management modality for patients with chronic liver disease. Reported herein is a case involving the marked rapid growth of HCC detected at an advanced stage in a screening test with a 3 months interval. A 49-year-old male patient with chronic hepatitis B was admitted to the hospital due to a liver mass detected on CT scan. The patient underwent a first CT scan 3 months earlier, and no tumor was detected. Follow-up CT scan was performed and showed a 9.1 cm HCC with portal vein thrombosis. Percutaneous liver biopsy was performed, and the diagnosis of hepatocellular carcinoma was confirmed. In the pertinent guidelines, the recommended screening interval for HCC is 6-12 months, but the screening interval and additional diagnostic methods should be considered due to the variation in the HCC growth rate according to the patient's clinical characteristics.

Hepatocellular Carcinoma with Bile Duct Tumor Thrombi.: Hye Sun Shin, Ji Young Hong, Jung Woo Han, Fa Mee Doh, Gi Jeong Kim, Do Young Kim, Sang Hoon Ahn, Gi Hong Choi; Yeungnam Univ J Med. 2011;28(2):180-186. Published online December 31, 2011; DOI: https://doi.org/10.12701/yujm.2011.28.2.180

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Obstruction of the bile duct owing to the direct extension of a tumor is occasionally found in patients with a hepatic neoplasm, but bile duct tumor thrombus caused by the intrabiliary transplantation of a free-floating tumor is a rare complication of hepatocellular carcinoma. A 50-year-old woman was diagnosed with HCC with bile duct tumor thrombi. She received transarterial chemoembolization (TACE) because her liver function was not suitable for surgery at the time of diagnosis. After TACE, infected biloma occurred recurrently. Thus, resection of the HCC, including the bile duct tumor thrombi, was performed. Six months after the surgery, recurred HCC in the distal common bile duct as drop metastasis was noted. The patient was treated with tomotherapy and has been alive for three years as of this writing, without recurrence. The prognosis of HCC with bile duct tumor thrombi is considered dismal, but if appropriate procedures are selected and are actively carried out, long-term survival can occasionally be achieved.

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Lipiodol-induced pneumonitis following transarterial chemoembolization for ruptured hepatocellular carcinoma
Haewon Kim, Yong Hoon Kim, Hong Jin Yoon, Kwang Hoon Lee, Seung Moon Joo, Min Kwang Byun, Jung Il Lee, Kwan Sik Lee, Ja Kyung Kim
Yeungnam University Journal of Medicine.2014; 31(2): 117. CrossRef

Dynamic CT Finding of Pelioid HCC; Case Report.: Rak Chae Son, Jae Woon Kim, Jae Chun Chang; Yeungnam Univ J Med. 2010;27(2):146-149. Published online December 31, 2010; DOI: https://doi.org/10.12701/yujm.2010.27.2.146

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Abstract PDF: Pelioid hepatocellular carcinoma (HCC), a type of atypical HCC, is a rare histologic type of HCC. The radiologic findings of the pelioid HCC is differ from the typical type of HCC. To our knowledge, this case report is the second literature to show the enhancing features of a pelioid HCC on dynamic computed tomography (CT). Here we describe the dynamic CT findings in a case of surgically confirmed pelioid HCC.

A Case of Hepatocellular Carcinoma with intradural growth Presenting as Obstructive Jaundice.: Sung Bum Kim, Tae Nyeun Kim, Sung Jun Kim, Ho Chan Lee, Jae Hyun Park, Jong Ryul Eun, Byung Ik Jang, Heon Ju Lee, Sung Su Yun, Young Kyung Bae; Yeungnam Univ J Med. 2008;25(2):165-170. Published online December 31, 2008; DOI: https://doi.org/10.12701/yujm.2008.25.2.165

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Abstract PDF: The incidence of hepatocellular carcinoma presenting as obstructive jaundice is 0.7~9%. The mechanisms of obstructive jaundice include bile duct invasion by tumor, tumor thrombi, blood clots, direct bile duct compression by tumor, and intraductal tumor growth. We report a rare case of hepatocellular carcinoma with intraductal growth. A 46-year-old woman was admitted due to colicky right upper abdominal pain and jaundice for 4 days. Computed tomography showed dilatation of the left intrahepatic duct, and endoscopic retrograde cholangiography showed a filling defect in the left main intrahepatic duct. We performed a left lobectomy with a Roux-en-Y hepaticojejunostomy. The tumor was diagnosed as a hepatocellular carcinoma with intraductal growth.

Review

Long Term Effects of Lamivudine and Adefovir dipivoxil in Chronic Hepatitis B Patients on the Development of Hepatocellular Carcinoma.: Heon Ju Lee; Yeungnam Univ J Med. 2008;25(1):1-18. Published online June 30, 2008; DOI: https://doi.org/10.12701/yujm.2008.25.1.1

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Abstract PDF: Although Lamivudine and adefovir dipivoxil are efficacious drugs for preventing hepatocellular carcinoma (HCC) in chronic hepatitis B patients, their efficacy is far from completely satisfactory. The risk of liver cirrhosis and HCC begins to increase at an HBV DNA level of 10(4) copies/ml. Even with latent or past HBV infection, episomal covalently closed circular DNA(cccDNA) plays a key rolein the persistence, relapse and resistance of HBV in its natural course or during therapy. The annual incidence of HCC in YUMC is 1.8% and 4.7% patients/year in the antiviral treatment and control groups, respectively. The ability to achieve a high rate of sustained HBV suppression with low risk of drug resistance is the ultimate goal in the treatment of chronic HBV infection. The efficacy of universal immunization with striking reductions in the prevalence of HBV in localized countries needs to be spread worldwide. With hepatitis B immunization and effective antiviral therapy, global control of HBV infection and HBV-related complications, including HCC, are possible by the end of the first half of the 21st century.

Original Article

The Role of Radiotherapy in Treatment of Hepatocellular Carcinoma.: Jong Ryul Eun, Kyo Won Choi, Heon Ju Lee, Mung Se Kim; Yeungnam Univ J Med. 2000;17(2):137-145. Published online December 31, 2000; DOI: https://doi.org/10.12701/yujm.2000.17.2.137

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Abstract PDF: BACKGROUND
Hepatocellular carcinomal(HCC) has been considered to be relatively radioresistant. The role of radiotherapy(RT) in the treatment of HCC is controversial. But RT has a role in the treatment of hepatocellular carcinoma as a single or combination modalities. The effect of radiotherapy on HCC was evaluated. Patients and METHODS: From January 1984 through January 2000, a total of 18 patients with unresectable HCC underwent radiotherapy alone or in conjunction with transarterial embolization(TAE). We reviewed the medical ecords of patients treated with RT and measured the tumor size using measured the tumor size using planimetry method. The Kaplan-Meier method was used to calculate the survival rate. RESULTS: The RT patients were 15 men and 3 women. The mean age was 51 years. four(22.2%) of them were accompanied with ascites. Eleven(61.1%) of them were accompanied with liver cirrhosis and their functions were 6, 3, 2 in each Child-Pugh A, B, C, respectively. A partial response(PR) was observed in 2 patients(11.1%), minimal response(MR) in 4 patients (22.2%) and no change(NC), in 11 patients(61.1%), whereas progressive disease(PD) was seen in 1 patients(6%), respectively. CONCLUSIONS: Although the radiotherapy in HCC did not improve the survival rate. it decreased the tmor size. Radiotherapy strengthens the therapeutic efficacy when combined with TAE, but more studies are needed.

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