台灣癌症醫誌 (J. Cancer Res. Pract.) 2(3), , journal homepage:
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1 台灣癌症醫誌 (J. Cancer Res. Pract.) 2(3), , 2015 DOI: /JCRP Case Report journal homepage: Sarcomatous Hepatocellular Carcinoma Wei-Cheng Lee 1,5, Chia-Chi Tsai 2,5, Tung-Ying Chen 3,5, Shin-Lin Shih 4,5, Horng-Yuan Wang 1,5, Shou-Chuan Shih 1,5, Chen-Wang Chang 1,5 * 1 Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan 2 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan 3 Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan 4 Department of Radiology, Mackay Memorial Hospital, Taipei, Taiwan 5 Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan Abstract. Sarcomatous hepatocellular carcinoma (HCC) is a rare subtype of hepatoma, along with worse prognosis than ordinary HCC. The risk of this subtype is still unknown, but some believed it has to be related to post anti-cancer therapy. We reported a case of sarcomatous HCC and the patient did not receive any anti-cancer therapy before. He came to our outpatient department due to symptoms of generalized malaise and poor appetite. One 10 cm in sized tumor was detected by ultrasound. He received surgical resection of the tumor but the tumor recurred after 3 months, with multiple metastases to peritoneum and brain. However, even under aggressive treatment, patient still expired in 6 months after operation. We reviewed several reports of this subtype of HCC. It was known that sarcomatous HCC is hard to be distinguished with ordinary HCC before surgery. There is no evidence that adjuvant therapy including chemotherapy, radiotherapy and target therapy may improve the survival rate. It would usually be diagnosed as atypical HCC and treated as ordinary HCC, however, the prognosis is much worse; this sarcomatosis type HCC should be seriously considered. 病例報告 Keywords : hepatocellular c sarcomatosis 肝癌合併肉瘤組織變化 李偉誠 1,5 蔡家麒 2,5 陳冬英 3,5 施焄鏻 4,5 王鴻源 1,5 施壽全 1,5 章振旺 1,5 * 1 台北馬偕醫院腸胃內科部 2 台北馬偕醫院一般外科部 3 台北馬偕醫院病理科部 4 台北馬偕醫院放射科部 5 馬偕醫護管理專科學校 中文摘要我們報告一個臨床上較為罕見的病例, 一個 65 歲男性有慢性 B 型肝炎但卻沒有規則追蹤, 因為食慾不振且體重減輕去門診求診時意外發現一 10 公分大的肝臟腫瘤 電腦斷 Open access under CC BY-NC-ND license.
2 256 W. C. Lee et al./jcrp 2(2015) 層並沒有明顯的動脈相顯影及非動脈性不顯影等典型肝癌的特徵 AFP 有升高所以臨床上還是認為疑似肝癌 經開刀切除後病理證實為一種具有肉瘤變化的肝癌 Hepatoma with sarcomatous change 此病患在開完刀三個月後腫瘤就復發, 且多處轉移至腹腔及腦部, 雖然經積極治療包括標靶藥物 Nexavar 及電療, 病患依舊於手術後 6 個月死亡 討論部分提到, 這種肝癌據過去統計占所有肝癌的 5-14%, 預後極差 相比一般的肝癌, 有肉瘤變化的肝癌也有較高的肝外轉移率及肝門靜脈侵犯的機率 較低的 2 年存活率及肝移植機率 遺憾的是, 此種患者在用傳統診斷肝癌的工具如超音波,AFP 電腦斷層甚至核磁共振上都沒有太專一性的表現可以與一般的肝癌鑑別 只有一篇文章由 Ijichi 在 2012 年提到用 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) 可以在術前鑑別肝癌是否有肉瘤變化 但這部分還需要更多研究去證實 關鍵字 : 肝細胞癌 c 肉瘤狀變化 INTRODUCTION It is known that hepatocellular carcinoma (HCC) may present with various histological features and has several subtypes, such as scirrhous HCC, fibrolamellar carcinoma, combined HCC-cholangiocarcinoma (HCC-CC), sarcomatoid HCC, undifferentiated carcinoma, and lymphoepithelioma-like HCC. These subtypes of HCC have variable clinical manifestation and growth rates. Sarcomatosis is one subtype of HCC, which has been reported sporadically before. Its clinical character is difficult to distinguish from ordinary HCC s, such as symptoms, elevated Alpha FetoProtein, or by abdominal sonography. Dynamic Computed tomography or MRI usually shows hepatic mass without typical HCC characteristic and they were frequently mis-diagnosed as atypical HCC. The correct diagnosis usually was made by pathology after operation. However, the prognosis of sarcomatous HCC is much poorer than ordinary type or any other subtypes of HCC. Rapid recurrence with high distant metastasis rate would be noted soon after operation. Survival length may not even make to 6 months. *Corresponding author: Chen-Wang Chang M.D. * 通訊作者 : 章振旺醫師 Tel: ext.3993 Fax: mky378@yahoo.com.tw We reported this case to remind clinical physicians the characters and clinical progress of this subtype of HCC. Poor prognosis should be mentioned when diagnosis confirmed. We also discussed the possibility of image diagnosis before pathologic studies. CASE REPORT A 65-year-old male had history of hepatitis B infection without regular follow up. He worked in China for a long time and suffered from poor appetite and weight loss about 10 kg in one month and visited a local hospital. Abdominal ultrasound showed a mix echoic lesion in the left liver, size about 10.2*6.8 cm, suspected to be malignancy and he was transferred to our hospital. When admitted, physical examination showed mild distention of the abdomen without tenderness. HBsAg and Anti-HBeAg were both negative. AFP was 183 ng/ml (Reference range < 10 ng/ml). Abdominal CT showed a heterogeneous hypodense tumor in the left lobe of liver (size about 11*8.8 cm) with peripheral contrast enhancement in arterial and portal phases but without peripheral contrast enhancement in delay phase. No regional lymphadenopathy is shown in CT scan (Figure 1A). Clinical stage is T3aN0M0 (stage IIIa) in TNM classification system. Persistent fever (>38 C), leukocytosis, WBC /ul (Reference range 4000~10000 / ul) and high CRP level, mg/dl (Reference range < 0.80 mg/dl) were found during hospitalization. Surgical
3 W. C. Lee et al./jcrp 2(2015) A 257 B Figure 1. (A) CT scan of liver after enhancement on portal phase revealed a hypodense mass in the left lobe of liver before surgery. (B) CT scan of liver after enhancement on portal phase revealed multiple recurrent tumors and another small one in the right lobe of liver 3 months after surgery excision of the left hepatic tumor by total left lobectomy was done smoothly and then fever subsided. The pathology showed multiple spindle shaped cells (Figure 3B) and multiple typical HCC cells (Figure 3A), which suggested both characters of sarcoma and hepatoma in this tumor. Furthermore, the sarcomatous component is diffusely positive for Vimentin stain (Figure 3C) and focally positive for HepPar-1 (Figure 3D), which proved the sarcomatous part is originating from hepatocellular carcinoma rather than from other origin or primary sarcoma. Surgical free margin is 5 mm. The HCC grading is Grade IV. One major branch of portal vein is involved. The stage of fibrosis in the non-tumor part is none to moderate fibrosis (Ishak score 0-4) (F2). The Necroinflammatory score of non-tumor part is 12/18, calculated by MODIFIED HAI GRADING system (Moderate piecemeal necrosis: Figure 2. CT scan of brain with enhancement revealed 3, Zone 3 necrosis with occasional portal-central (P-C) an enhanced nodular lesion with perifocal bridging:4, five to ten foci focal (spotty) lytic necrosis, edema at junction of right frontal and parie- apoptosis and focal inflammatory per 10x objective: 3, tal lobes moderate portal inflammation:2). AFP declined to 6.39 ng/ml (Reference range < 10
4 258 W. C. Lee et al./jcrp 2(2015) A B C D Figure 3. (A) Epithelioid cells with abundant cytoplasm and high grade nuclei (H&E 200X). (B) Proliferation of malignant spindle cells with tumor necrosis (Left upper part, Arrow area) (H&E 200X). (C) Malignant spindle cells are diffusely positive for vimentin immunohistochemical stain (200X). (D) Some tumor cells are positive for HepPar-1 immunohistochemical stain (200X) ng/ml) after surgery and he was discharged under sta- patient had received target therapy (Sorafenib) 800 mg ble condition. Further treatment including chemo- per day and radiotherapy for brain metastasis but the therapy or target therapy was not initiated right after response was poor. He expired about six months after surgery due to the National Health Insurance policy in surgery. Taiwan and patient s economic condition. However, three months later, abdominal CT was DISCUSSION arranged again and showed multiple recurrent tumors Sarcomatous hepatocellular carcinoma (HCC) is in right liver and abdominal cavity (Figure 1B). Left very rare but gradually increasing in prevalence dur- lower leg weakness was also mentioned and brain CT ing recent dozen years. Study by Kojiro had revealed showed a possible metastatic lesion in the junction of that sarcomatous HCC accounted for 5.9% of total right frontal lobe and parietal lobe (Figure 2). The HCC during the 12 years from 1969 to 1980, and
5 W. C. Lee et al./jcrp 2(2015) % of total HCC during the 6 years from 1983 to 1989 [1]. The cause of increasing incidence is hard to know because of the low incidence of sarcomatous HCC, but some believed it was related to anti-cancer therapy such as trans-arterial embolization (TAE), percutaneous ethanol injection therapy (PEIT) and even radiofrequency ablation (RFA) [1-3]. For example, a study published by Kojiro in 1989, analyzing 579 autopsy cases of hepatocellular carcinoma (HCC), with 55 cases (9.4%) exhibited a sarcomatous appearance. They found sarcomatous appearance in 20.9% of the cases undergoing anticancer therapy and in 4.2% of the cases not undergoing anticancer therapy [1]. It is hard to diagnose this subtype of HCC before pathology. Two previous studies before 2010 even claimed that there is no way except biopsy to distinguish between sarcomatous and ordinary HCC [4,5]. Fortunately, some image characters of sarcomatous HCC were under analyzed. For example, typical sarcomatosis HCC in dynamic CT usually showed peripheral enhancement with an unenhanced central portion, compatible with the fibrous stroma in the periphery and central necrosis in the tumor [6]. Typical MRI would show a mass with low T1 and high T2 signal intensity, with some intratumoral cystic lesions [7]. A Japanese author H. Honda published a study in 1996, compare the image character of sarcomatous HCC and ordinary HCC by analyzing 6 sarcomatous HCC patients. All these tumors had peripheral enhancement on delayed CT images. Lymphadenopathy was observed in 100% (six of six patients) and intrahepatic metastases were observed in 83% (five of six). Both metastatic lesions had peripheral enhancement, just like their primary hepatic tumors. Although peripheral enhancement on early CT images could also be observed in hemangiomas (56%), metastases (29%), and in intrahepatic cholangiocarcinomas(15%), however, the peripheral enhancement on delayed CT images was more commonly seen in sarcomatous HCC (100%) than in those other tumors (18%, 11%, 5%) [8]. Besides, some other image tools used to distinguish sarcomatous HCC to ordinary HCC were also applied clinically. One recent study by Ijichi in 2012 had mentioned that 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was a good tool to detect sarcomatous HCC. In his study, maximum standardized uptake value (SUVmax) of sarcomatous hepatocellular carcinoma is higher. This above finding may be useful in differentiating HCCSC from combined hepatocellular and cholangiocarcinoma, undifferentiated HCC, moderately and poorly differentiated HCC. High SUV max values represented poor prognosis. Although the expansive cost and not popularity of FDG-PET limited the clinical application in worldwide, however, FDG-PET could be considered as an effective and non-invasive tool to evaluate the aggressiveness of primary HCC with typical CT or MRI findings [6]. Pathology of sarcomatous HCC usually reveals sarcomatous appearance include anaplastic spindleshaped cells forming interlacing bundles with a partial storiform pattern. The spindle-shaped cells have an eosinophilic cytoplasm, ovoid or long nuclei, with marked anisocytosis and frequent mitoses [9]. Currently, treatment of sarcomatous HCC is similar to ordinary HCC but the prognosis of sarcomatous HCC is much worse. As previous studies revealed, sarcomatous HCC had higher rate of extrahepatic metastases (46%) and portal invasion (62%) than ordinary HCC [9,10]. 2-year survival rate after resection (25%) and liver transplantation (33%) were also low in patients of sarcomatous HCC within the Milan criteria [4]. Radical resection of early stage tumor seemed to be the best treatment for sarcomatous HCC. Transarterial embolization (TAE), trans-arterial chemotherapy embolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) is not considered to be effective due to poor vascularity and poor enhancement in CT arterial phase. Kato, Y., K. had reported one case in 2011, who had a huge hepatoma with
6 260 W. C. Lee et al./jcrp 2(2015) focal sarcomatous change receiving HAIC (using 5- fluorouracil and cisplatin). Poor response was noted and patient died in 8 months after diagnosis [11]. The role of systemic adjuvant chemotherapy is still under debated. Tsuji, Y., K. had reported one case of sarcomatosis HCC, with a 23 x 13 x 23 cm tumor, originated from segments IV and VII of the liver, and grew extrahepatically. Right side diaphragm infiltration was also noted during operation. Resection of the involved segment and diaphragm was performed and they arranged combination chemotherapy (etoposide, epirubicin, and cisplatin). No recurrence for 12 months after surgery was noted [12]. Although one case report may not make this systemic chemotherapy as a standard treatment, frustratingly, there is no better way for treatment currently so far. We reported one patient with sarcomatous HCC. And we might try this regimen in the next feasible case. REFERENCES 1. Kojiro M, Sugihara S, Kakizoe S, et al. Hepatocellular carcinoma with sarcomatous change: a special reference to the relationship with anticancer therapy. Cancer Chemother Pharmacol 23 Suppl: S4-8, Komada N, Yamagata M, Komura K, et al. Hepatocellular carcinoma with sarcomatous change arising in primary biliary cirrhosis. J Gastroenterol 32: , Koda M, Maeda Y, Matsunaga Y, et al. Hepatocellular carcinoma with sarcomatous change arising after radiofrequency ablation for well-differentiated hepatocellular carcinoma. Hepatol Res 27: , Hwang S, Lee SG, Lee YJ, et al. Prognostic impact of sarcomatous change of hepatocellular carcinoma in patients undergoing liver resection and liver transplantation. J Gastrointest Surg 12: , Said Y, Trabelsi S, Kourda N, et al. Hepatocellular carcinoma with sarcomatous change. Tunis Med 88: , Ijichi H, Shirabe K, Taketomi A, et al. Clinical usefulness of (18) F-fluorodeoxyglucose positron emission tomography/computed tomography for patients with primary liver cancer with special reference to rare histological types, hepatocellular carcinoma with sarcomatous change and combined hepatocellular and cholangiocarcinoma. Hepatol Res May 43: 481-7, Chung YE, Park MS, Park YN, et al. Hepatocellular carcinoma variants: radiologic-pathologic correlation. AJR Am J Roentgenol 193: W7-13, Honda H, Hayashi T, Yoshida K, et al. Hepatocellular carcinoma with sarcomatous change: characteristic findings of two-phased incremental CT. Abdom Imaging 21: 37-40, Maeda T, Adachi E, Kajiyama K, et al. Spindle cell hepatocellular carcinoma. A clinicopathologic and immunohistochemical analysis of 15 cases. Cancer 77: 51-7, Da Ines D, Bailly A, Lannareix V, et al. Hepatocellular carcinoma with sarcomatous change: prompt and fatal intraabdominal recurrence after liver transplantation. Gastroenterol Clin Biol 33: 590-3, Kato Y, Matsubara K, Akiyama Y, et al. Direct biliopancreatoduodenal invasion by hepatocellular carcinoma: report of the first resected case and review of the literature. Int J Clin Oncol 16: 421-7, Tsuji Y, Okada K, Fukuoka M, et al. Hepatocellular carcinoma with a sarcomatous appearance: report of a case. Surg Today 31: 735-9, 2001.
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