© 2004 Foundation for Promotion of Cancer Research
A Case of Postoperative Recurrence of Fibrolamellar Hepatocellular Carcinoma with Increased Vitamin B12 Binding Capacity in a Young Japanese Female
1 Department of Surgery, Hiratsuka City Hospital, Hiratsuka, Kanagawa and 2 Clinical Laboratories, National Tokyo Medical Center, Tokyo, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
|---|
A 17-year-old Japanese female underwent major hepatic resection for a huge fibrolamellar hepatocellular carcinoma that was compressing the inferior vena cava. The tumor was not exposed at the surgical margin but was very close to it. A recurrent lesion at the surgical margin of the liver and a lymph node metastasis were discovered 9 months postoperatively together with a marked elevation of vitamin B12 binding capacity. These lesions were resected, and vitamin B12 binding capacity decreased thereafter. Peritoneal dissemination was detected by CT 16 months postoperatively, together with recurrent elevation of vitamin B12 binding capacity. Several types of chemotherapy, including intraperitoneal injection of epirubicin, were applied and improved the patient’s quality of life somewhat, but the patient died of recurrent disease 34 months after the initial hepatic resection. This is the first report in Japan of fibrolamellar hepatocellular carcinoma with increased vitamin B12 binding capacity as a useful marker. Fibrolamellar hepatocellular carcinomas, if resected, have a better prognosis than ordinary hepatocellular carcinoma in Japan, as well as in Western countries. An aggressive strategy should be chosen, which consists mainly of precise surgical resection and postoperative multimodality therapy, including chemotherapy.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
|---|
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC) which is histologically characterized by eosinophilic neoplastic hepatocytes separated into cords by lamellar fibrous strands (1–3). FLHCC is known to be relatively common in Western countries but very rare in Asian countries such as Japan (1–5). FLHCC often develops at a young age and resected cases have a relatively good prognosis (4,5); several markers, including neurotensin and vitamin B12 binding capacity, have recently attracted attention as tumor markers of FLHCC (1,6).
We encountered a case of typical FLHCC in a young Japanese woman whose primary tumor was resected but recurred in the remnant liver, a lymph node and the peritoneal cavity, and in which vitamin B12 binding capacity was useful in evaluating tumor progression. We previously reported this case in Japanese after the initial operation, focusing mainly on imaging diagnosis (7). This is a follow-up report where we describe the case in English and review and discuss the Japanese-published literature.
|
CASE REPORT |
|---|
|
TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
|---|
A 17-year-old Japanese female presented with right chest pain and hepatomegaly in August 1996 and was admitted to our hospital. Laboratory tests showed mild elevations of GOT (AST) (58 IU/l), GPT (ALT) (72 IU/l) and inflammatory markers, including C-reactive protein and the erythrocyte sedimentation rate, and the fibrinogen level (768 mg/dl) was markedly elevated. Total bilirubin and ICG15 were normal. Serological viral markers (HBsAg and HCVAb) were negative and tumor markers (AFP, PIVKA-2, CEA and CA19-9) were all within normal limits.
Enhanced computed tomography (CT) disclosed a huge, solid liver tumor, 15 cm in diameter, in segments 4 and 8 (Fig. 1). The tumor had a lobulated boundary and showed mixed density. The characteristic central scar with calcification was also demonstrated. A preoperative diagnosis of malignant hepatic tumor with impairment of protein synthesis and clinical manifestations of caval compression was made, and surgery was planned in September 1996.
|
The tumor was huge and was located in segments 8, 4 and 2. It was compressing the right and left hepatic veins and had involved the middle hepatic vein. Extended left lobectomy that included subsegment 8 was performed. On gross examination, the tumor was 12 x 9 cm in size, was clearly demarcated and had a lobulated boundary (Fig. 2). The tumor exhibited prominent stromal fibrosis, a central scar and compartments showing hemorrhage, necrosis and bile production. In contrast to ordinary HCCs, it did not bulge up on the cut surface, reflecting its fibrous character. The surrounding background liver was essentially non-cirrhotic. No portal tumor thrombi and intrahepatic metastases were detected. The tumor was not exposed at the surgical margin, but was very close to it.
|
Microscopically, the tumor cells were relatively large and polygonal and the cytoplasm was eosinophilic and granular (Fig. 3). The nucleoli were prominent, and pale bodies and globular hyaline bodies were also seen. Bile plugs were seen in the tumor cells. Electron microscopy revealed abundant mitochondria. Prominent stromal fibrosis exhibited the ‘lamellar’ pattern throughout the tumor, and nests of tumor cells were divided by the lamellar fibrosis. There was no microscopic evidence of inflammatory changes, including lymphocyte infiltration or fibrosis, in the portal tract of the background liver. The tumor was ultimately diagnosed as a typical FLHCC. The patient was discharged from the hospital on postoperative day 26.
|
Follow-up CT in June 1997 disclosed a recurrent lesion, 2 cm in diameter, near the surgical margin of the remnant liver, and a 2.5 cm lymph node metastasis was detected near the common hepatic artery (Fig. 4). Marked elevation of unsaturated vitamin B12 binding capacity was also observed (Fig. 5). Partial resection of segment 7 of the liver together with the diaphragm and lymph node dissection was performed in July 1997. Pathological examination confirmed the lesions to be a recurrence of FLHCC (Fig. 6). The recurrent tumor exhibited characteristic fibrolamellar pattern, but it did not contain a central scar.
|
|
|
The level of vitamin B12 binding capacity returned to normal within a month after the second resection, but it rose again in December 1997 (Fig. 5). A CT scan disclosed multiple recurrent tumors in the peritoneal cavity, and a third laparotomy in January 1998 revealed multiple disseminated tumors in the peritoneal cavity. One of them was biopsied and submitted to histoculture drug response assay (HDRA) to evaluate the in vitro chemosensitivity of the tumor (8). The inhibition index was 86.7% with 5-fluorouracil (5FU), 82.5% with doxorubicin and 59.5% with cisplatin. Inpatient systemic chemotherapy with 40 mg of epirubicin (an isomer of doxorubicin) and 700 mg of 5FU was administered intravenously on days 1 and 8, with daily oral administration of 100 mg cyclophosphamide on days 1–14. Subsequent chemotherapy with these three agents was continued in the outpatient clinic until June 1998.
Ascites developed due to peritoneal dissemination and, when intraperitoneal injection of cisplatin was ineffective, 40 mg of epirubicin was administered intraperitoneally twice, in July and in August 1998. This regimen was effective, and the ascites was controlled thereafter. Intravenous epirubicin was added in October and November 1998. Extremely elevated levels of vitamin B12 binding capacity (>12 000 pg/ml) were found from March 1998 onward. However, the sequential chemotherapy, mainly with epirubicin, afforded the patient a relatively comfortable and stable life for approximately one year, despite the peritoneal dissemination. She was finally readmitted for massive tumor growth in the peritoneal cavity, and she died in August 1999.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
|---|
Edmondson first described FLHCC as a distinct pathological entity in 1958, which was subsequently confirmed by Craig et al. and Berman et al. (1–3). FLHCC is defined as ‘a slowly growing, expanding tumor with septate fibrosis arising in normal liver and is characterized by eosinophilic neoplastic hepatocytes separated into cords by lamellar fibrous strands’ (1).
The incidence of FLHCC is relatively high in Western countries, where it accounts for around 10% of all HCCs (3,4), but is low in Asian countries (1), where the prevalence of ordinary HCC arising in chronic viral liver disease is high. It is also very rare in Japan with only 15 typical cases having been reported in full papers (Table 1). Several cases thought to have developed in cirrhotic liver or capable of being categorized as the sclerosing type of HCC were excluded (1).
|
A review of the Japanese cases revealed an age range of 15–45 years, with a mean age of 21.9 years, and there was no difference in incidence according to sex. These findings are similar to those reported in Western countries (1–5). The tumors were usually large, with tumors >10 cm in diameter in 73% of the patients, similar to the 75% of cases in the category reported by Ringe et al. (4). A central scar and calcification within the tumor are important pathological findings for making the diagnosis, and they were detected in 11 (73%) and seven cases (47%), respectively (1).
Elevation of PIVKA-2 in seven cases (64%) was noteworthy as a serological marker of FLHCC, especially in the AFP-negative cases. Elevated vitamin B12 binding capacity has been reported as a specific marker of FLHCC and is thought to be due to production or modification of the binding protein transcobalamin I by the tumor (6). Since the level of vitamin-B12 binding capacity in our case was elevated when the tumor recurred and decreased after tumor reduction, the trend reflected tumor mass volume and disease progression, making vitamin B12 binding capacity useful as a marker of FLHCC. This is the first report of a case of FLHCC with elevated levels of vitamin B12 binding capacity in Japan.
Surgical resection is the treatment of first choice for FLHCC, and because FLHCCs tend to be large and locally extended, major hepatic resections are required in most cases (Table 1). Despite these efforts, the surgical margins of the resected specimens were usually very close to the tumor (71% of the reported cases), and incomplete resection resulted in local recurrence. Lymph node metastasis was frequent, occurring in 47% of cases, it has also been reported in Western countries (4,5). The pattern of recurrence of FLHCCs differs from that of ordinary HCCs, which is characterized by the frequent occurrence of portal tumor thrombi and intrahepatic metastases, but in which lymph node metastases are rare. Peritoneal dissemination is rare in both ordinary HCCs and FLHCCs, except in cases where tumors rupture. Tumor implantation during the surgical procedure is a possible pathological mechanism of liver recurrence near the surgical margin and of peritoneal dissemination, especially in our case. Because of this, the most significant strategy for cure is major hepatic resection, with the aim of precise local control of tumors with a negative surgical margin, adequate lymph node dissection, and without implantation of tumor cells. Several authors have reported a better outcome after hepatic resection, with a 5-year survival rate of 62.5% as reported by Berman et al. (3) and 40% by Ringe et al. (4), and a 32-month median survival time (2).
Even after recurrence, FLHCCs tend to have good prognosis. Multimodality treatment should be considered for patients with recurrent disease (5), and chemotherapy should be chosen to control disease progression in addition to repeated resection, as in our case. We used HDRA to select an appropriate agent, and since the tumor showed good chemosensitivity to doxorubicin, we used epirubicin, an isomer of doxorubicin, as the main agent of chemotherapy, and obtained an improvement in the patient’s quality of life.
We have reported a typical case of FLHCC and reviewed the cases reported in Japan. This is the first report of a Japanese case of FLHCC in which increased vitamin B12 binding capacity was a useful marker. Japanese FLHCCs resemble those in Western countries in terms of resected cases having a better prognosis. An aggressive strategy for longer survival that mainly includes surgical resection with precise local control, especially at the surgical margin, lymph node dissection and postoperative multimodality treatment, such as additional resection and chemotherapy, should be adopted.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Toshio Kanai, Department of Surgery, Hiratsuka City Hospital, 19-1, Minamihara-1, Hiratsuka, Kanagawa 254-0065, Japan. E-mail: kaitosh{at}mb.scn-net.ne.jp
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
|---|
1 Craig JR, Peters RL, Edmondson HA. Fibrolamellar hepatocellular carcinoma. In: Tumors of the liver and intrahepatic bile ducts. 2nd Series. Washington, DC: Armed Forces Institute of Pathology. 1989; pp.171–9.
2 Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 1980;46:372–9.[CrossRef][Web of Science][Medline]
3 Berman MM, Libbey NP, Foster JH. Hepatocellular carcinoma Polygonal cell type with fibrous stroma—an atypical variant with a favorable prognosis. Cancer 1980;46:1448–55.[CrossRef][Web of Science][Medline]
4 Ringe B, Wittekind C, Weimann A, Tusch G, Pichlmayr R. Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surg Gynecol Obstet 1992;175:299–305.[Web of Science][Medline]
5 Epstein BE, Pajak TF, Haulk TL, Herpst JM, Order SE, Abrams RA. Metastatic nonresectable fibrolamellar hepatoma. Am J Clin Oncol 1999;22:22–8.[CrossRef][Web of Science][Medline]
6 Paradinas FJ, Melia WM, Wilkinson ML, Portmann B, Johnson PJ, Murray-Lyon IM, et al. High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J 1982;285:840–2.
7 Yamazaki H, Kohda E, Kanai T, Ishikawa H, Kuramochi S, Hasagawa I, et al. A case report of fibrolamellar hepatocellular carcinoma. Jpn J Clin Radiol (Rinsho Hoshasen) 1998;43:523–6 (in Japanese).
8 Furukawa T, Kubota T, Hoffman RM. Clinical applications of the histoculture drug response assay. Clin Cancer Res 1995;1:305–11.[Abstract]
9 Taniura H, Nagasue N, Kohno H, Kanamori H, Nakamura T, Nagaoka S. A case report of fibrolamellar carcinoma of the liver. Jpn J Gastroenterol Surg 1987;20:2627–30 (in Japanese).
10 Tanaka J, Baba N, Arii S, Fujita K, Tamura J, Kawakami Y, et al. Typical fibrolamellar hepatocellular carcinoma in Japanese patients: Report of two cases. Surg Today 1994;24:459–63.[CrossRef][Web of Science][Medline]
11 Beppu T, Kubota T, Katafuchi S, Honma K, Matsumura F, Takeguchi T, et al. A resected case of fibrolamellar carcinoma in the liver—a distinctive features in diagnostic imagings. Acta Hepatol Japon (Kanzo) 1995;36:601–7 (in Japanese).
12 Hasegawa A. Fibrolamellar hepatocellular carcinoma: a report of a resected case with an electron microscopic and flow cytometric analysis. Pathol Int 1996;46:84–90.[Web of Science][Medline]
13 Yamamoto H, Watanabe K, Nagata M, Yano Y, Akai T, Honda I, et al. Transformation of fibrolamellar carcinoma to common hepatocellular carcinoma in the recurrent lesions of the rectum and residual liver: a case report. Jpn J Clin Oncol 1999;29:445–7.
14 Tomimuro T, Kayama H, Funai S, Kou K. A resected case of fibrolamellar carcinoma of the liver. Nihon Gekakei Rengou Gakkaishi 1999;24:797–801 (in Japanese).
15 Hiramatsu K, Okamoto K, Uesaka K, Mukaiyama H, Seno T. Surgical management for lymph node recurrence of resected fibrolamellar hepatocellular carcinoma: a case report. Hepatogastroenterology 1999;46:1160–3.[Medline]
16 Yamaguchi R, Tajika T, Kanda H, Nakanishi K, Kawanishi J. Fibrolamellar carcinoma of the liver. Hepatogastroenterology 1999;46:1706–9.[Medline]
17 Nojiri T, Mitsumori N, Yoshida T, Shinohara T, Asakura J, Doi N, et al. A case of fibrolamellar hapatocellular carcinoma. Jpn J Gastroenterol Surg 2000;33:1905–9 (in Japanese).
18 Magata S, Kitahara K, Watanabe K, Miyazaki K. Fibrolamellar hepatocellular carcinoma—a case report. Acta Hepatol Japon (Kanzo) 2001;42:414–9 (in Japanese).
19 Yoshinaga Y, Okazumi S, Takayama W, Makino H, Iwasaki K, Kondou S, et al. A resected case of fibrolamellar hepato cellular carcinoma in a 15 year old woman. Shoukaki Gazou 2002;4:97–103 (in Japanese).
20 Yoshimi F, Asato Y, Amemiya R, Itabashi M, Nakamura K. Fibrolamellar hepatocellular carcinoma in a Japanese man: report of a case. Surg Today 2002;32:174–9.[CrossRef][Web of Science][Medline]
21 Sugihara A, Nakasho K, Yamada N, Iwasaki T, Tsujimura T, Tsuji M, et al. A case of recurrent fibrolamellar hepatocellular carcinoma: immunohistochemical study. Shindan Byori 2002;19:338–42 (in Japanese).
Received January 9, 2004; accepted March 14, 2004
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||