Fibrolamellar carcinoma: a review with focus on genetics and comparison to other malignant primary liver tumors

Fibrolamellar carcinoma is a rare primary malignant liver neoplasm that usually affects adolescents and young adults with no underlying liver disease. Morphologically, the tumor cells resemble oncocytic hepatocytes arranged in cords with a stroma of lamellated collagen fibers. Immunohistochemical studies have found that fibrolamellar carcinomas express markers associated with both biliary (CK7 and epithelial membrane antigen) and hepatocytic (heppar-1and glypican-3) differentiation, as well as markers associated with hepatic progenitor cells (CK19 and EpCAM) and stem cells (CD133 and CD44). Genetic studies show fewer alterations compared with classic hepatocellular carcinoma. Pooled data from comparative genomic hybridization studies show that fibrolamellar carcinomas have fewer and less frequent genomic alterations when compared with classic hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma. Of the alterations seen in fibrolamellar carcinoma, the most frequent are gains in 1q and 8q (also frequently seen in other hepatic tumors) and loss of 18q. Fibrolamellar carcinoma also has less frequent methylation of tumor suppressor promoters compared with hepatocellular carcinoma and minimal alterations in mitochondrial DNA. Fibrolamellar carcinoma is associated with better survival than hepatocellular carcinoma and cholangiocarcinoma, presumably due to the young age of the patients and the lack of cirrhosis. These features make more aggressive surgical therapy possible. There is currently very little information on the effectiveness of chemotherapy for fibrolamellar carcinoma.     

Fibrolamellar hepatocellular carcinoma with a recurrence of classic hepatocellular carcinoma: a case report and review of Oriental cases

A 72-year-old Chinese male, hepatitis B carrier, received a right hepatic trisegmentectomy in 1997 for fibrolamellar hepatocellular carcinoma. Serum alpha-fetoprotein was in the normal range until two years after the operation, a rapid increase to 241 ng/mL occurred and computed tomography showed a 2-cm-sized recurrent nodule in the caudate lobe. Because computed tomography arterioportography showed additional multifocal nodules in the residual liver, transarterial embolization was performed. Four months after the first transarterial embolization, the caudate tumor grew to 6 cm and serum alpha-fetoprotein increased to 6090 ng/mL. Prior to the second transarterial embolization, this new hepatic lesion received a biopsy and showed a characteristic feature of classic hepatocellular carcinoma, which was different from the previous one. Four months after the second transarterial embolization, computed tomography showed no recurrent tumor and serum alpha-fetoprotein subsequently normalized. Twenty-two months after the first transarterial embolization, a 2.5-cm-sized tumor recurred again at the lateral segment. At this time, serum alpha-fetoprotein (3.6 ng/mL) was not elevated. He received the third transarterial embolization and is still alive. Recurrence of fibrolamellar hepatocellular carcinoma after hepatic resection has been reported to be high, but a case report with a character of muticentric, multifocal, and metachronous recurrences of fibrolamellar and classic type hepatocellular carcinoma is very rare. This is the second case report in the literature.     

Recurrent fibrolamellar hepatocellular carcinoma with biliary invasion: Successful resection

A jaundiced 17-year-old man was diagnosed as having a local recurrence of fibrolamellar hepatocellular carcinoma 2 years and 4 months after left hepatic trisegmentectomy with total caudate lobectomy had been performed. The patient had a tumor occupying the upper part of the extrahepatic and intrahepatic bile ducts. Complete resection of the recurrent tumor was carried out. The patient remains well 3 years after the second surgery. Fibrolamellar hepatocellular carcinoma, a rare type of liver cancer, is a well defined disease entity with distinct clinical and histopathological features and a favorable prognosis. The good prognosis seems to warrant aggressive surgical intervention in patients with recurrences. Therefore, additional surgery for tumor recurrence should be considered. To our knowledge, this is the first report of a case in which a recurrent tumor of fibrolamellar hepatocellular carcinoma invaded the entire bile duct wall was successfully resected.     

Fibrolamellar hepatocellular carcinoma

Fibrolamellar hepatocellular carcinoma is an uncommon malignancy seen in young adults without underlying liver disease. Physical signs are minimal and laboratory values are noncontributory. Diagnosis is suggested by clinical history, supported by radiographic studies, and confirmed by histologic examination. Individuals with fibrolamellar carcinoma generally have a greater survival than those with hepatocellular carcinoma. Although most patients with fibrolamellar carcinoma undergo curative surgery, two of the three patients we report had inoperable tumors.     

Fibrolamellar carcinoma of the liver.

We report a resected case of fibrolamellar carcinoma (FLC) of the liver that occurred in a 21 year-old Japanese male with a normal liver. Lymph node metastases around the common hepatic artery and the hepatic hilum were revealed by a post-operative histological examination. He was in good health 7 months after the surgery. This case demonstrates typical findings of FLC, radiologically and histologically. The details are described in this report. Moreover, after reviewing 12 Japanese cases, we emphasize the differential diagnosis of focal nodular hyperplasia (FNH) as the following: 1) Calcification is frequently seen in FLC. 2) The central scar of FLC is visualized as an area of low intensity on T2-weighted magnetic resonance imaging (MRI).     

A resected case of fibrolamellar hepatocellular carcinoma with chronic hepatitis (type B)]

We report a case of a 34-year-old woman who tested positive for HBs Ag with fibrolamellar hepatocellular carcinoma of the liver. The sister of this patient, who was also positive for HBs Ag, died of hepatocellular carcinoma (HCC). The patient showed elevation of alpha-fetoprotein. Abdominal CT scan showed a tumor in the posterior segment of the liver and hepatic angiography revealed marked neovascularity in the tumor. Partial resection of the liver was performed, and the histological diagnosis was fibrolamellar hepatocellular carcinoma. The patient is now tumor free and doing well 20 months after the operation.     

Liver resection in advanced hepatocellular carcinoma

BACKGROUND/AIMS: The aim of this study was to assess the results of major liver resection in patients with advanced hepatocellular carcinoma in terms of safety and survival. METHODOLOGY: The subjects of this study are 19 patients that underwent 24 resections for advanced (stage IV) hepatocellular carcinoma. Eighteen of these resections were performed for primary tumor and 6 were repeat resections. Nine patients presented without cirrhosis, 5 with cirrhosis, and 5 patients had the fibrolamellar variant of hepatocellular carcinoma. RESULTS: Hospital mortality was recorded in 1 case (5%). Morbidity was noted in 7(37%) cases. All patients with fibrolamellar variant of hepatocellular carcinoma are alive at 78, 41, 24, 12 and 9 months (P = 0.008), compared with a median survival of 18 and 9 months for the noncirrhotic hepatocellular carcinoma and cirrhotic hepatocellular carcinoma groups, respectively (P = 0.24). CONCLUSIONS: We conclude that an aggressive policy of major liver resection with vascular reconstruction was justifiable in patients with advanced fibrolamellar variant of hepatocellular carcinoma and in selected patients with noncirrhotic hepatocellular carcinoma, and of doubtful value in patients with cirrhosis.     

Fibrolamellar hepatocellular carcinoma: report of a case

We report a case of fibrolamellar hepatocellular carcinoma, which occurred in a 58-year-old man with normal liver function. Preoperative ultrasonography, computed tomography and magnetic resonance imaging depicted a large tumor in the left lateral segment, which was compatible with the typical radiological features of fibrolamellar hepatocellular carcinoma. He underwent left lobectomy and no lymphadenopathy or distant metastasis was demonstrated. Macroscopic findings of the resected liver demonstrated a well-defined whitish-yellow tumor with a central scar. Microscopic findings of the tumor showed cords of tumor cells, which were surrounded by abundant collagenous fibrous tissue arranged in a lamellar distribution. He has been doing well for approximately one year since the surgery without any signs of recurrence. In addition, we discuss the clinicopathological features of fibrolamellar hepatocellular carcinoma based on a review of 22 Japanese patients who have been previously reported.     

Fibrolamellar hepatocellular carcinoma in pregnancy

BackgroundHepatocellular carcinoma (HCC) is rare in pregnancy but can enlarge rapidly under these circumstances.Case outlineA 25-year-old woman was diagnosed with HCC of fibrolamellar type immediately post-partum. One year after liver resection the patient remains well.DiscussionThis is only the second report of fibrolamellar carcinoma occurring in pregnancy. Other types of hepatocellular carcinoma in pregnancy have generally demonstrated a poor outcome, probably secondary to hormonal changes and increased liver vascularity.     

Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy. Identification of two groups of patients with prospects for prolonged survival

Among 37 patients with hepatocellular carcinoma given systemic chemotherapy, 12 (32 percent) lived 14 to 37 months from initiation of treatment whereas the remainder died within five months. Individual factors associated with improved survival included fully ambulatory performance status, lack of jaundice, response to chemotherapy, the fibrolamellar carcinoma pathologic variant, absence of cirrhosis, and normal serum alpha-fetoprotein levels. Patients living longer than 12 months fell into two groups. Seven patients with fibrolamellar carcinoma lacked evidence of hepatitis B serum markers or cirrhosis and had normal alpha-fetoprotein levels and surprisingly frequent extrahepatic metastases. All but one were Caucasians aged 25 years or less. The other five "long-term" survivors were all fully ambulatory without jaundice, and the majority were older non-Caucasians with tumor confined to the liver at the time of diagnosis and with hepatitis B markers, elevated alpha-fetoprotein levels, or cirrhosis. All patients without fibrolamellar carcinoma who were less than fully ambulatory or who had jaundice died quickly. Patients with fibrolamellar carcinoma have homogeneous clinical features, and their disease follows a relatively indolent course. In other patients with hepatocellular carcinoma, assessment of ambulatory status and serum bilirubin determination can identify those with some prospect of prolonged survival.     

Hepatocellular carcinoma in the youth. A comparative analysis with hepatocellular carcinoma in adulthood

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a very rare disease among young individuals. Epidemiological, clinical and histopathological features of this malignancy in the youth have not been thoroughly studied. METHODOLOGY: A review of the clinical files of patients with HCC younger than 40 years of age, who were treated between May 1990 and July 2002, was performed. RESULTS: Seventeen patients were included for analysis; nine were female and eight male. The mean age at diagnosis was 24 years (range 12-39 years). Abdominal pain was the main symptom, followed by vomiting and nausea. Enlargement of the liver was observed in 11 patients (65%). In seven patients (41%), an etiological factor was not found. Five of these cases were of the fibrolamellar variant (29%). Only four patients were resected (23%) two of which belonged to the fibrolamellar type. Three patients (18%) are still alive after 64.9 months of follow-up. CONCLUSIONS: HCC is a very uncommon disease in the youth and affects similarly both genders. It is discovered at an advanced stage. Hepatitis B and C are uncommon etiological factors. The frequency of fibrolamellar carcinoma is higher in this age group. Though resection is more feasible, the overall survival rates remain low.     

Recurrent obstructive jaundice caused by fibrolamellar hepatocellular carcinoma

Summary A 24-year-old man with hepatocellular carcinoma presented with recurrent obstructive jaundice caused by bile duct invasion and distal migration of necrotic tumor fragments. After resection of an isolated left lobe tumor, he was well for 2 years until he again presented with obstructive jaundice caused by necrotic tumor and clot in the common bile duct. Analysis of his tumor revealed the fibrolamellar histologic variant of hepatocellular carcinoma. This case is unique in that the hepatocellular carcinoma was of the fibrolamellar variant and presented both intially and when recurrent 2 years later with obstructive jaundice caused by invasion of the common bile duct.     

Hepatocellular carcinoma in women: probable lack of etiologic association with oral contraceptive steroids

To investigate the possibility of an association between oral contraceptive steroids (CS) and hepatocellular carcinoma (HCC), we reviewed 128 cases of HCC in women collected between 1953 and 1980. There were 48 cases under the age of 40, and 13 of these (27%) had used CS. However, 62% of HCC associated with CS and 58% of HCC in women under 40 not using CS were classified histologically as "fibrolamellar" carcinoma. This subtype of HCC occurs predominantly in young people, both male and female. The apparent increase in HCC in young women can be explained by the presence of cases of fibrolamellar carcinoma in this age group, an the apparent association with CS is probably coincidental.     

Bilateral adrenal metastases from hepatocellular carcinoma after liver transplantation

Therapeutic management of hepatocellular carcinoma is a controversial issue. Orthotopic liver transplantation is an alternative for the treatment of hepatocellular carcinoma in a selected group of patients, but recurrence is possible. A 51-year-old patient with liver transplantation due to hepatocellular carcinoma presented bilateral adrenal metastases in a successive manner. A left adrenal gland metastasis was diagnosed five months after liver transplantation, and a left adrenalectomy was carried out. Eight months later, a right adrenal gland metastasis was diagnosed, and a right adrenalectomy was performed. Pathological examination confirmed the diagnosis of a well-differentiated hepatocellular carcinoma. At present, there is no evidence of recurrence 35 months after the second adrenalectomy. Bilateral adrenal gland metastases from hepatocellular carcinoma after liver transplantation have not been previously reported in English literature. Surgical resection of metastases may be indicated in similar patients with successful treatment of the primary tumor, absence of additional metastasic disease, and good performance status.     

Glutathione treatment of hepatocellular carcinoma

ABSTRACT— This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of GSH daily from the time of diagnosis. Two patients withdrew shortly after receiving GSH due to intolerable side-effects. Of the six eligible patients, two had mildly advanced tumors and four moderately advanced tumors. At 1–2-month intervals the liver was CT and ultra-sound scanned to assess the growth status of the tumor (progression, stagnation or regression). All the patients, except a male with a fibrolamellar type of HCC, died within 1 year after diagnosis. Two women with moderately advanced tumors survived almost 1 year, tumor growth stopped or regressed and in one of the women an initially abnormal alfa-1-fetoprotein (AFP) returned to normal after GSH treatment. AFP remained normal throughout the treatment period in the other woman. These observations indicate that GSH may have a sex-dependent effect on HCC. However, further studies involving more patients are required to pursue this hypothesis.     

Transformation of p53-positive papillary thyroid carcinoma to anaplastic carcinoma of the liver following postoperative radioactive iodine-131 therapy

Multiple liver metastases were incidentally detected in the lobe of the liver of an 81-year-old woman following total thyroidectomy and ablative radioactive iodine administration for the treatment of papillary thyroid carcinoma. A biopsy specimen taken from the metastatic liver tumor was histologically diagnosed as anaplastic carcinoma. Immunohistochemical staining for p53 was positive in both the primary tumor and liver biopsy specimens. We considered this to have been caused by anaplastic transformation from papillary thyroid carcinoma during treatment. We report a rare case of multiple liver metastases from a papillary thyroid carcinoma, which we believe to be the result of anaplastic transformation during postoperative radioactive iodine-131 therapy.     

Blocking alpha2 integrins on rat CC531s colon carcinoma cells prevents operation-induced augmentation of liver metastases outgrowth

Currently, an operation is the only curative option for patients with colorectal cancer. Unfortunately, many patients will develop liver metastases even after successful resection of the primary tumor. Removal of primary colorectal carcinoma may paradoxically increase the risk of metastases development, because accumulating evidence suggests that surgical trauma can stimulate tumor growth. In the present study, we investigated the effects of abdominal trauma on liver metastases development. Surgical trauma dramatically increased adhesion of tumor cells in the liver, leading to enhanced outgrowth of metastases. Endothelial stress was observed rapidly after an operation, suggesting that abdominal trauma resulted in impairment of blood vessel integrity. Tumor cells preferentially adhered to extracellular matrix (ECM). Furthermore, preincubation of tumor cells with anti-alpha2 integrin antibodies completely reverted operation-induced augmentation of CC531s adhesion and liver metastases outgrowth. As such, we postulate that blood vessel integrity in the liver is compromised after abdominal trauma, resulting in enhanced ECM exposure, which enables tumor cell adhesion and metastases outgrowth. Conclusion: Perioperative treatments that either aim to reduce endothelial stress or block the interaction between tumor cells and ECM represent promising new therapeutic strategies for the prevention of liver metastases development after resection of the primary tumor.     

The time of occurrence of liver metastasis in carcinoma of the pancreas

Summary By measuring the doubling time of liver metastasis, the authors investigated the possibility of occult liver metastasis at the time of pancreatectomy in patients with pancreatic carcinoma. We calculated tumor doubling times of liver metastases in six patients after pancreatectomy for periampullary carcinoma and compared with cell doubling times. We also calculated the diameters of the occult liver metastases at the time of pancreatectomy on the assumption that the growth rates of liver metastasis were constant. Tumor doubling times of liver metastases in six patients were 34, 32, 318, 108, 78, and 27 d, respectively. In two of these patients, tumor doubling times, compared with cell doubling times of 51 and 52 h for PK-36 and PK-59 established from the same patients with carcinoma of the pancreas, were about 15 times as long as those of cultured cell lines. The calculated sizes of the occult liver metastases at the time of pancreatectomy in these six patients were 2.4, 0.14, 19.0, 8.2, 3.5, and 4.2 mm. In five of these six patients, the calculated sizes were in the range between 10 μm and 1 cm. These results indicated occult liver metastases had already existed in patients with carcinoma of the pancreas at the time of pancreatectomy and were too small to be detected by imaging technique. We cannot improve survival rates in carcinoma of the pancreas by surgical management alone. For further improvement in survival rate of patients with carcinoma of the pancreas to occur, effective adjuvant therapies to prevent liver metastases must complement surgical management.     

A case of endocrine cell carcinoma (small cell carcinoma) of duodenum]

Extra-ampullary duodenal endocrine cell carcinoma is extremely rare. A 65-year-old woman visited our hospital, complaining of epigastralgia, anorexia and vomiting. She was admitted for suspected duodenal or pancreas head tumor by abdominal CT. Fiberscopic examination revealed a circumferential tumor in the extra-ampullary duodenal second portion. Histopathological findings of biopsy specimen showed a small cell carcinoma, and positive immunohistochemical staining for synaptophysin revealed this tumor to be endocrine cell carcinoma. Pylorus-preserving pancreaticoduodenectomy with partial transversocolectomy was performed, and intraoperative washing cytology detected tumor cells in the peritoneal cavity. Although she discharged from hospital uneventfully, she died 11 months later of multiple liver metastases and peritoneal dissemination. This case showed the high malignant potential of this tumor.     

Octreotide-sensitive ectopic ACTH production by islet cell carcinoma with multiple liver metastases

We report a 21-year-old woman with ectopic ACTH syndrome due to islet cell carcinoma with multiple liver metastases. On admission, she showed Cushingoid appearance (moon face, central obesity etc.) and had acute respiratory distress syndrome due to pneumocystis carinii pneumonia. Laboratory examination revealed marked elevations of plasma ACTH (735 pg/ml) and cortisol (145 microg/dl) with a profound hypokalemia (2.0 mEq/l). She was found to have multiple masses in the liver and a solid mass in the tail of pancreas by abdominal computerized tomography scanning. Treatment with octreotide successfully reduced elevated plasma ACTH and cortisol levels, and she received frequent transhepatic arterial embolization and chemotherapy. The primary pancreatic tumor was surgically removed, revealing islet cell carcinoma which contained high content of ACTH (100 microg/g wet weight) and abundantly expressed proopiomelanocortin and somatostatin receptor subtype-2 mRNAs as determined by Northern blot analysis. Postoperatively, she was free from symptoms for almost one year. However, progressive enlargement of multiple liver metastases refractory to chemotherapy led her to decide on total hepatectomy and liver transplantation from her father. After liver transplantation, she remained almost free from symptoms for almost one year. However, metastases developed to the mediastinal and paraaortic lymph nodes as detected by 111[In] pentetreotide scintigraphy. Eleven months after liver transplantation, she was again treated with octreotide and, 16 months after, with metyrapone, both of which were effective in reducing ACTH and cortisol levels, respectively, until she died of acute respiratory failure. This case of a young female patient with ectopic ACTH-producing islet cell carcinoma of the pancreas was quite unique in that she survived for 5 years despite the acute onset and rapid progression of the multiple liver metastases at least in part due to the long-lasting favorable response to octreotide and living-related liver transplantation.