Fibrolamellar Carcinoma Research Articles

Copper and copper-binding protein in liver tumors.

The presence of copper and copper-binding protein was histochemically investigated in 39 hepatocellular carcinomas, 24 metastatic tumors of the liver, and eight benign hepatic tumors. None of the hepatocellular carcinomas was fibrolamellar. The presence of copper (demonstrated by rhodanine) and of copper-binding protein (demonstrated by modified orcein) was simultaneously observed in 11 of the 39 hepatocellular carcinomas (28%). Deposition was mild in three cases, moderate in two cases, and marked in six cases, and it was significantly related to the presence of bile within the tumor. Copper and copper-binding protein granules were not found in metastatic tumors of the liver, and were observed in two of the eight cases of benign hepatic tumors. These results suggest that the presence of copper and copper-binding protein in tumor cells may be found in all variants of hepatocellular carcinomas and not only in fibrolamellar carcinomas as previously suggested, and might be helpful in differentiating primary from secondary liver tumors.

Fibrolamellar Carcinoma of The Liver — A Case Report From Japan and a Review of The Literature

The first Japanese case of fibrolamellar carcinoma (FLC) of the liver is described. The 17-year-old Japanese male affected died of the disease 25 months after palliative operation. The diagnosis of FLC had not been confirmed before autopsy. Pre-operative diagnosis of FLC is important to surgeons. Acccording to the literature, FLC is rare in Asia. The endemic discrepancy may suggest that the carcinogenic factors are different from those of general hepatocellular carcinoma.

Fibrolamellar carcinoma as a cause of bile duct obstruction

Obstructive jaundice due to growth within bile ducts of hepatocellular carcinoma is uncommon and usually a manifestation of advanced, lethal tumour. We report a case of fibrolamellar carcinoma of the liver presenting with obstructive jaundice, caused by tumorous permeation of the left hepatic duct with migration of tumour fragments into the common bile duct. Immunocytochemical and ultrastructural features are described. Two and a half years after complete surgical resection the patient is free of tumour. The importance of accurate diagnosis of such tumours is emphasized.

4 Tumour markers in diagnosis and management

The 20-year period since the discovery of AFP by Abelev has seen the introduction of a wide range of new tumour markers and it is now clear that PLC is biologically heterogeneous. Hepatoblastomas, fibrolamellar carcinomas, hepatocellular carcinomas and cholangiocarcinomas may secrete a variety of distinctive markers which are predominantly glycoproteins, and may resemble those found in placenta or fetal liver. Diagnostically, AFP remains the best marker for HCC, both in sensitivity and specificity; it is known to consist of isoforms. In patients with elevated serum AFP and filling defects on liver scan, Con A reactive AFP may differentiate PLC from hepatic metastases, whilst fucosylated AFP may distinguish PLC from benign disorders when AFP is non-diagnostically elevated. With this recognition of tumour heterogeneity the value of a multiplemarker approach has become apparent. The measurement of vitamin B 12 binding protein and neurotensin should lead to the detection of most patients with the fibrolamellar variant of HCC and many of these should be resectable. In patients with normal serum AFP levels, HCC-associated GGTP is of major value whilst in low-incidence areas for HCC, patients should also be screened for H-ALP; using a multiple marker approach in high-risk groups, 90% of clinically diagnosed hepatocellular carcinomas are serologically positive. The Chinese and Alaskan studies, in which small, potentially resectable tumours were detected, suggest that it is now possible to achieve 5-year survival figures of up to 60% in HCC patients detected by screening. The value of such a strategy in low-incidence countries is currently under study. In patient monitoring, as in diagnosis, AFP remains the outstanding marker. In AFP-negative patients, other markers including vitamin B 12binding protein, neurotensin, HCC-specific isoenzymes, des-γ-carboxy-prothrombin and α-fucosidase, are of undoubted diagnostic value, but their value as indicants of disease progression remains to be established. In monitoring the response of hepatic metastases, CEA remains the least unsatisfactory marker but should always be used in conjunction with serial ultrasound scans. Tumour markers now play an important role in the diagnosis and monitoring of PLC but a role is also emerging in tumour imaging and drug targeting. The next 20 years should see the introduction of tumour markers of high sensitivity and specificity which make a fundamental contribution not only to detection and monitoring, but also to the effective treatment of liver cancer.

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Fibrolamellar Carcinoma of the Liver in a Child

We describe a fibrolamellar carcinoma of the liver in a 12-year-old girl and review the literature concerning the occurrence of this distinct hepatic neoplasm in children up to the age of 16 years. The results of our electron microscopic and immunohistologic studies suggest that some cells of this tumor exhibit neuroendocrine differentiation. This finding has important theoretical implications relative to the tumor's histogenesis and practical implications with respect to the search for tumor markers of clinical usefulness and possibly for therapy.

A profile of primary hepatocellular carcinoma patients in the Gizan Area of Saudi Arabia

Clinical, laboratory, and ultrasonographic features of 75 patients of primary hepatocellular carcinoma (PHC) living in the Gizan Area of Saudi Arabia and their follow-up, during a 2-year period, were characterized. Eighty-nine percent of the cases were defined histologically, whereas in the rest, ultrasonographic (US) evidence along with an alphafetoprotein (AFP) level exceeding 480 ng/ml were taken as the positive evidence for PHC. Eighty percent of the cases were male patients, with the peak incidence during the seventh decade. The most common clinical presentations were hepatic enlargement (91%), abdominal pain (76%), splenic enlargement (33%), and acites (33%), followed by bruit, fever, metastases, and varices. Alteration in a liver function test was manifest in 97% of the cases, AFP values greater than 480 ng/ml in 57%, and a hepatitis B virus surface antigen (HBsAg) positivity in 65% of the cases. There was no intersex variation in positivity for HBsAg, antibody to HBsAg (anti-HBs), antibody to hepatitis B virus core antigen (anti-HBc) among the 30 PHC cases studied. Positivity for HBsAg or the overall hepatitis B virus exposure in PHC cases was higher than the normal controls (P less than 0.001). In addition to histologic confirmation of PHC in 67 cases, there was histologic evidence of cirrhosis in 25%, or chronic active hepatitis in 19% of the cases. At the time of diagnosis, the average duration of the presenting illness was less than 2 months, while the mortality in the ensuing 2-month period was 73%. The average span of total illness in the vast majority of cases was 4 to 6 months. Two female patients (one with fibrolamellar carcinoma) however, survived for 2 years. Immunization against hepatitis B virus should be considered for all newborns in such hyperendemic communities. A continuous program should be started in such communities to screen and immunize all those yet unexposed to hepatitis B virus. The established HBsAg carriers should be periodically examined ultrasonographically along with an AFP estimation for initiating the chemotherapeutic and other measures against PHC in fairly early stages of malignancy.

Hepatoblastoma and hepatocarcinoma in children: Analysis of a series of 29 cases

Twenty-nine cases of liver malignancies, 26 hepatoblastomas (HB) and 3 hepatocarcinomas (HC), were treated in a 13-year period. All children were submitted to operation but four had nonresectable tumors, even after chemotherapy. Surgery in the 25 cases consisted of right lobectomy in 14, a left lobectomy in 9, and a tumorectomy in 2; a secondary operation had to be performed in 5 cases, either because of histologic doubt on the cut section of the presumed normal parenchyma, or for local recurrence. Preoperative chemotherapy, instituted on a routine basis since 1982, did appear to facilitate surgery in otherwise inoperable tumors. The benefits of preoperative embolization, done for three children, were minimal. Ten children died, one in the immediate postoperative period, eight others from the disease, and one from a complication of chemotherapy. Follow-up for the 18 surviving children, all recurrence and metastasis-free, with normal alphafetoprotein (AFP) is less than 2 years for four and from 2 to 11 years for 14. One teen-age girl, with a fibrolamellar carcinoma has just recently been reoperated because of recurrence three years later. In spite of the fact that 6 out of 7 children operated without adjunctive treatment are cured, a systematic course of preoperative chemotherapy has been prescribed in the more recent cases. Follow-up for these is yet too short.

Characteristics of fibrolamellar hepatocellular carcinoma: A study of nine cases and a review of the literature

Clinical and laboratory data for nine patients with hepatocellular fibrolamellar carcinoma treated at our institution have been summarized with emphasis on the relevance of plasma neurotensin levels as a tumor marker. The mean age of the patients was 22 years. Seven underwent hepatic resection, and two of these had later surgical removal of recurrent disease. Plasma neurotensin levels were initially elevated in five of the seven patients in whom it was measured. Neurotensin levels were within normal limits in three of four patients with recurrent disease, but were elevated in one patient who also had elevated plasma neurotensin levels preoperatively. In addition, a review of 80 patients reported since 1980 was performed. The mean age of these patients was 23 years, and only 6 percent were older than 50. The male to female ratio was 3:4. Eight percent were positive for hepatitis B antigen and 11 percent had elevated α-fetoprotein levels. Four percent had cirrhosis of the liver. The resectability rate was 58 percent. Five year survival for patients who underwent hepatic resection was 56 percent. Patients treated nonsurgically had a median survival of 13 months, and none of these patients lived for 5 years. Fibrolamellar hepatoma seems to be a distinct clinical entity that mainly occurs in young patients. The prognosis in patients treated with a curative resection is good. Plasma neurotensin levels may be of value as a tumor marker, but further studies are necessary to substantiate this theory.

Mitochondrial abnormalities in hepatocytes adjacent to fibrolamellar hepatocellular carcinoma.

A light and electron microscopic study was undertaken on a surgical specimen of a hepatic fibrolamellar carcinoma with special emphasis on the mitochondrial changes in nontumor hepatocytes. The tumor, both light and electron microscopically, showed typical features for this special variant neoplasm. The nontumor liver maintained normal architecture with marked lymphoid hyperplasia and fibrosis in the portal regions in the vicinity of the tumor. No megamitochondria were appreciated under the light microscopic examination. The electron microscopic observation, however, revealed prominent morphological alterations of individual mitochondrion. The dividing mitochondria were frequently found. Pseudoinclusions or invaginations of the membrane were common. Many mitochondria were enlarged with various shapes. The cristae were disordered and crystalloid material was easily observed. The possible significance of these mitochondrial abnormalities in nontumor hepatocytes was discussed.

Copper and hepatocellular carcinoma.

The presence of copper and copper-binding protein (CBP) within tumor cells was searched by histochemical methods (rhodanine, rubeanic acid and Shikata's orcein) in a group of 39 autopsies, all consecutive cases of hepatocellular carcinoma (HCC) associated with cirrhosis (HCC + C). In 2 cases, fibrolamellar carcinoma (FLC) not associated with cirrhosis was observed at surgery. Considerable amounts of copper and CBP were found within tumor cells only in the 2 FLC cases and in 1 HCC + C case, in a portion of the tumor showing FLC-like features. Copper-positive tumor cells had an oncocytic appearance, which was confirmed by ultrastructural examination. In 64% of the HCC + C cases (25 out of 39), copper and CBP deposits were found in nonneoplastic hepatocytes mainly distributed along the periphery of cirrhotic nodules. The present study indicates that the storage of copper inside tumor cells is a peculiarity of the FLC type of HCC with a close relationship to the oncocytic nature of neoplastic hepatocytes. The significance of copper deposits in nonneoplastic cirrhotic hepatocytes remains a matter for further investigations.

Review of Three Cases and the Presentation of a Characteristic Set of Tumor Markers Defining this Tumor

This study demonstrates the unique clinical and histologic aspects of fibrolamellar hepatic carcinoma, a rare variant of hepatocellular carcinoma. Three cases are reviewed and an extensive study of immunologic and intracellular substances defining this tumor is presented. Length of survival was considerably longer than typical hepatoma. The cause of death generally is due to a lack of control of the primary tumor. Successful treatment appears to relate to the ability to perform a total excision of the primary hepatic tumor. Chemotherapy should be used only in the presence of metastatic disease. Surgical resection of metastatic disease, unlike the usual hepatocarcinoma, may have some beneficial use. Fibrinogen was found in all tumors. It is possible that this tumor produces fibrinogen to create its unique histologic appearance. Carcinoembryonic antigen is described for the first time in this tumor. Both deposits of alpha-1 antitrypsin and copper were found in most of the tissues studied. The presence and amounts of these substances differ markedly from the common type of hepatoma. This unique composition of intracellular components may both facilitate histologic diagnosis, particularly if the amount of tissue is limited, and give further insight into the etiology of this tumor.

Fibrolamellár hepatocellular carcinoma. An immunohistochemical and ultrastructural study

Two cases of fibrolamellar carcinoma of the liver are reported in young female patients of 12 and 21 years of age. Small amounts of perinuclear alpha-fetoprotein were found, unrelated to hyaline globules, as well as alpha 1-antitrypsin in a periglobular fashion in isolated cells. Ferritin was present in a large number of cells. Ultrastructurally, the well differentiated nature of the neoplasm was substantiated by previously unreported findings such as intercellular lumina analogous to bile canaliculi and peroxisome-like bodies containing a central crystalloid. Filamentous material resembling Mallory's type of hyaline was also found. We conclude that both immunohistochemical and ultrastructural features reflect a high degree of differentiation.

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-fetoproteln 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 alphafetoprotein 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 billrubin determination can identify those with some prospect of prolonged survival.

Thirty years of experience with pediatric primary malignant liver tumors

Since 1950, 48 infants and children from 10 weeks to 16 years of age presented with primary hepatic malignancy. Signs and symptoms ranged from asymptomatic to those of malignant disease. All patients had a palpable abdominal mass. Jaundice was seen in five patients, four of whom had preexisting cirrhosis. Three male children had evidence of precocious puberty. Whereas liver function tests were usually normal, alpha-fetoprotein levels, when elevated, proved useful diagnostically and as a tumor marker in follow-up. Hepatic angiography and computed tomography (CT) scans have provided the most valuable preoperative assessment of hepatic architecture. Sixteen infants and children underwent resection for cure. Eleven of these patients are alive and disease free 6 months to 23 years later. Six additional patients had incomplete resection with subsequent radiotherapy and/or chemotherapy; only one such patient is disease-free past 3 years. Twenty-six tumors could only be biopsied; most of these patients died within 12 months regardless of what treatment they received. The histology was hepatoblastoma in 39 patients, hepatocellular carcinoma in 4, fibrolamellar carcinoma in 4, and malignant mesenchymal tumor (mesenchymoma) in 1. The patients with hepatocellular carcinoma and mesenchymoma all died. Three of four patients with fibrolamellar carcinoma are alive and disease-free following resection up to 3 years; this histology seems favorable. The other survivors had hepatoblastoma. The role of adjunctive chemotherapy and/or radiotherapy has not yet been determined.

Evaluation of the clinical effectiveness of sperum CK-MB measurements on the dupont ACA for patients admitted to a coronary care unit

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-fetoproteln 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 alphafetoprotein 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 billrubin determination can identify those with some prospect of prolonged survival.

NEUROTENSIN SECRETION BY FIBROLAMELLAR CARCINOMA OF THE LIVER

Serum neurotensin concentrations were supranormal in 5 out of 20 patients with carcinoma of the liver. Liver specimens from 4 of these 5 patients demonstrated features typical of fibrolamellar carcinoma. Neurotensin may be suitable as a tumour marker for fibrolamellar carcinoma and may be useful for the detection of recurrences after treatment.

Hepatocellular carcinoma and oral contraceptives.

This article reports 11 new cases of liver cancer in US born women ages 18-39 occurring in 1975-80 obtained from the population-based cancer registry for Los Angeles County, California. 2 matched controls were obtained for each case. 10 cases had used OCs for periods ranging from 6-168 months, and 1 was given unspecified hormone shots for menstrual regulation during the 9 months preceding hormone shots for menstrual regulation during the 9 months preceding diagnosis of liver cancer. 6 were taking hormones at the time of diagnosis. The average duration of OC use among the 10 cases was 64.7 months compared with 27.1 months in controls (p0.005). Review of histopathologic material indicated that 3 cases had typical fibrolamellar carcinomas and 1 had a typical microtrabecullar carcinoma. 1 other case was a typical well-differentiated hepatocellular carcinoma. In 3 additional cases, the carcinoma was more undifferentiated but some trabecullar pattern was evident. The remaining 3 cases had distinctly unusual liver neoplasms, including a giant cell carcinoma, a sclerosing duct forming carcinoma, and a papillary carcinoma. The latter tumor occurred in a woman who had used OCs for 168 months. There was no evidence of exposure to other potential causes for liver cell carcinoma. The clinical, pathological, and epidemiological data strongly suggest that longterm OC use may cause hepatocellular carcinoma.

Hepatic neoplasia: Selected clinical aspects

Benign liver tumors are relatively uncommon and, even when large enough to be symptomatic, they usually remain undiagnosed prior to exploratory laparotomy. Hemangiomas constitute the majority of benign hepatic neoplasms and are 9 times as frequent in females as in males. Most are asymptomatic but abdominal swelling, a mass, or symptoms due to compression of adjacent organs may occur and abdominal hemorrhage is reported in 4.5% of patients. Hepatic hemangioma may produce a large arteriovenous communication serious enough to cause heart failure. Recently an increased frequency of liver tumors, mostly adenomas, has been noted in women taking oral contraceptives (OCs); the cause has been attributed to estrogens. The exact incidence is unknown but believed to be low. It is most common in women in their late 20s who have been on OCs for 7 years or more. The tumor occasionally completely regresses on withdrawal of the OCs. The tumor may be discovered incidentally at laparotomy or may manifest inself by pain, a palpable mass, or catastrophic hemoperitoneum. Hepatic adenoma is usually a solitary lesion and infrequently degenerates into malignancy. Differential diagnosis includes chronic gall bladder disease and peptic ulcer. Focal nodular hyperplasia (FNH) is apparently much less frequently related to OC use and is less likely to bleed seriously than adenoma. Hepatic chemistry is usually normal in adenoma and FNH, but slight increases in serum bilirubin, serum alkaline phosphatase, and serum transaminase may occur. Primary liver cancer (hepatocellular carcinoma or hepatoma) is mostly a disease of males and in the US and Western Europe seldom develops before age 40. Fibrolamellar carcinoma, which characteristically develops in adolescents and young adults, occurs with equal sex incidence. Doubt has been expressed about its relationship to OCs. In the US about 75% of primary hepatocellular carcinomas are associated with cirrhosis, and about 5% of cirrhosis cases develop primary liver cancer. Clinical manifestations of hepatoma have been divided into 5 groups: frank cancer (62.7%), acute abdominal cancer (8%), febrile cancer (8%), occult cancer (16%), and metastatic cancer (5%). Detection of large amounts of alpha fetoprotein has proven useful in diagnosis of hepatocellular carcinoma, but values may be negative in OC users. It has been estimated that 1/3 to 1/2 of all malignant tumors eventually metastasize to the liver.

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.