Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma.
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Carcinoma, Hepatocellular↗
Biomedical subjects
K G Ishak
Publications and source records attributed to K G Ishak.
Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study.
Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.
Aged↗
Expression of inhibin-alpha by granular cell tumors of the gallbladder and extrahepatic bile ducts.
This is the first report of inhibin-alpha expression in granular cell tumors. A Medline search of the literature revealed no case reports of granular cell tumors in any location of the body being tested for inhibin-alpha immunohistochemically, by enzyme-linked immunosorbent assay, by radioimmunoassay, or by immunoprecipitation. Seventeen cases of previously diagnosed granular cell tumors of the gallbladder and extrahepatic bile ducts with hematoxylin and eosin-stained sections, and S-100 protein immunostain were retrieved from the archives of the Armed Forces Institute of Pathology. All cases were reviewed for diagnostic accuracy and then immunostained for inhibin-alpha (with endogenous biotin blocking). All 17 (100%) cases were diffusely positive for inhibin-alpha immunostain. Previous studies of inhibin-alpha-positive lesions reported in the literature include sex cord stromal tumors (granulosa cell tumors, luteinized thecomas, Leydig cell tumors), placental and gestational trophoblastic lesions, and adrenal cortical tumors. This study adds the granular cell tumor to the list of inhibin-positive lesions and should prove helpful in differential diagnosis of these lesions.
Adolescent↗
Eosinophilic granuloma of the liver: a characteristic lesion with relationship to visceral larva migrans.
Children with the clinical syndrome of visceral larva migrans as a result of Toxocara species have typical lesions in the liver and other viscera, consisting of palisading granulomas that contain numerous eosinophils and often Charcot-Leyden crystals; recognizable parasites are uncommon. Similar eosinophilic granulomas that are found incidentally in adults often cause diagnostic problems. To define better the clinical, laboratory, and pathologic features of these lesions, we reviewed 43 cases of hepatic eosinophilic granuloma (excluding cases of Langerhans' cell histiocytosis) collected in the files of the AFIP over a period of 31 years. The eosinophilic granulomas were found in patients of all ages (range 12 months to 77 years); 30% were younger than 20 years. There were 26 male and 17 female patients. Most patients (26 of 43; 60%) were asymptomatic, and the lesions were discovered incidentally. Others had fever (20%) or abdominal pain (20%). The granulomas were typically multiple (61%), with central necrosis surrounded by a mixed inflammatory infiltrate with numerous eosinophils and variable numbers of neutrophils. lymphocytes, and a palisade of epithelioid histiocytes and/or giant cells. Charcot-Leyden crystals were present in 19 cases (44%). Remnants of parasites (eight Toxocara sp., two Capillaria sp.) were identified in the tissue in 10 patients. There was a positive serologic test for Toxocara sp. in five additional cases. Immunohistochemical staining using polyclonal antiserum against Toxocara canis larvae demonstrated positivity in macrophages in eight of 13 cases tested. We conclude that identification of an eosinophilic granuloma in the liver should suggest the diagnosis of visceral larva migrans and prompt a search for the causative organism with serial sectioning of the block and serologic tests for Toxocara and other causative parasites.
Adolescent↗
Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene.
Gap junctional intercellular communication is often impaired in cancers, and the genes which encode the connexin gap junction proteins are considered to be tumor-suppressor genes. In this study, we analyzed the presence of mutations in the connexin 37 (Cx37) gene in 22 human hepatic angiosarcomas, 6 and 4 of which were associated with exposure to vinyl chloride and Thorotrast, respectively. The other 12 samples were from patients with no history of exposure to these 2 agents. In 9 samples, a proline (ACC) to serine (ACT) amino acid change in codon 319 was detected. However, DNA from non-tumorigenic tissue of the same patients also showed this amino acid change, suggesting that this is a polymorphism rather than a mutation. Subsequent analysis of 84 DNA samples from normal donors revealed the frequencies of Pro/Pro, Pro/Ser and Ser/Ser alleles to be 65.5%, 23.8% and 10.7%, respectively, while among the group of angiosarcoma patients the corresponding figures were 59.1%, 31.8% and 9. 1%, respectively. Thus, there was no correlation between the polymorphism at codon 319 and hepatic angiosarcoma occurrence. However, among the 6 cases of vinyl chloride-associated angiosarcoma, the percentages of the polymorphic alleles were 33.3%, 66.7% and 0%, respectively. While the number of samples was too small to allow us to conclude that the Ser319 allele in Cx37 predisposes to this rare type of human cancer, it may be noted that codon 319 is located at the cytoplasmic tail of Cx37, where most regulatory sequences reside, and that it could be a site of phosphorylation for some protein kinases, which may in turn affect the function of Cx37, including intercellular communication.
Carcinogens↗
Clear cell carcinoma of the liver: a comparative immunohistochemical study with renal clear cell carcinoma.
Morphologic differentiation of clear cell hepatocellular carcinoma (HCC-CC) from clear cell renal carcinoma (RCC-CC) may not be possible without the aid of immunohistochemical stains. We performed a battery of immunohistochemical stains on 10 previously diagnosed HCC-CCs, and 10 RCC-CCs, in order to determine which single or combination of immunostains would be most useful in diagnosis. We concluded that a positive Hepatocyte immunostain (DAKO) is sufficient for a diagnosis of HCC-CC if enough tissue is available. This immunostain distinguishes HCC-CC from other clear cell malignancies with sensitivity of 90% and specificity of 100%, when biopsy material is adequate. Other tests were much less sensitive, although several had specificity of 100%. A negative immunostain does not exclude the diagnosis of HCC-CC (negative predictive value 91%, especially in small biopsy material) and should be followed by additional immunostains such as pCEA for demonstration of tumor canaliculi, ubiquitin for Mallory bodies, and several epithelial cell markers that are typically positive in RCC-CC (epithelial membrane antigen, Leu M-1, pancytokeratin) and negative in HCC-CC.
Adenocarcinoma, Clear Cell↗
Clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres: a novel member of the perivascular epithelioid clear cell family of tumors with a predilection for children and young adults.
The perivascular epithelioid cell family of tumors (PEComas), defined by their co-expression of melanocytic and muscle markers, includes angiomyolipoma, lymphangioleiomyoma, and clear cell "sugar" tumors of the lung, pancreas, and uterus. We present seven cases of a unique and previously unrecognized tumor of children and young adults, which represents a new addition to the PEComa group of tumors. Culled from three institutions over a 50-year period, all cases occurred in or immediately adjacent to the ligamentum teres and falciform ligament. Six patients were female and one male; their ages ranged from 3 to 21 years (median, 11 yrs). Tumor sizes ranged from 5 to 20 cm (median, 8 cm). All cases consisted of clear to faintly eosinophilic spindled cells arranged in fascicular and nested patterns. The cells had small but distinct nucleoli and low mitotic activity. Immunohistochemically, all cases were positive with antibodies to gp100 protein (HMB-45) and negative for S-100 protein. In three of the seven cases studied immunohistochemically, the tumors expressed smooth muscle actin, melan-A, microphthalmia transcription factor (MiTF), and myosin, but not desmin. No expression of the TSC2 gene product, tuberin, was seen in three cases. One case studied cytogenetically disclosed a t(3;10). Follow-up data, available in six of seven cases (median duration, 18 mos), showed five patients to be free of disease and one to have a radiographically presumed lung metastasis. We think these tumors comprise a new entity for which we propose the term "clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres." The differential diagnosis of these tumors includes clear cell sarcoma of tendons and aponeuroses, leiomyosarcoma, and angiomyolipoma.
Abdominal Neoplasms↗
Pathologic features of chronic hepatitis. A review and update.
The general histopathologic changes of chronic hepatitis and those related to the various causes are reviewed. Consideration also is given to underlying or associated diseases and to mixed infections in chronic viral hepatitis. Changes occurring in exacerbations or relapses are described. Selected histopathologic changes are illustrated. The nomenclature is reviewed briefly, with emphasis on separation of activity from stage of disease.
Hepatitis, Chronic↗
Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases.
BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare neoplasm of vascular origin that occurs in the liver and other organs; its etiology is unknown. METHODS: The authors analyzed the clinicopathologic and immunohistochemical features of 137 patients with EHE of the liver in an attempt to identify features that might predict tumor behavior. To their knowledge, this article represents the largest series reported from one institution. RESULTS: Patients were ages 12-86 years; 84 (61%) were females and 53 (39%) were males. They presented with nonspecific symptoms such as right upper quadrant pain or weight loss. Macroscopically, the tumors usually were multiple. They typically were white, firm to hard, and ranged in size from 0.2-14 cm. Histologically, the tumors were comprised of dendritic and epithelioid cells that often contained vacuoles representing intracellular lumina. The stroma was fibrous, with myxohyaline areas. Immunohistochemically, all tumors were positive for at least one endothelial marker (factor VIII-related antigen [FVIII-RAg], CD34, and/or CD31). Treatment modalities included hepatic resection or transplantation. Although the metastatic rate in this series was 27%, the prognosis is considered much more favorable than that of other hepatic malignancies. Twenty-six patients (43%) survived > or = 5 years; 2 patients were alive and well at last follow-up after 23 and 27 years, respectively. Twenty-six of 60 patients (43%) died of their disease, 1 of whom died 28 years after discovery of her tumor. In an attempt to predict behavior of the tumor, several histologic parameters were evaluated using univariate analysis. No significant correlation was found with mitoses, Glisson's capsule infiltration, or nuclear atypia. High cellularity was significantly correlated with a poor clinical outcome (P = 0.00012), whereas the association with tumor necrosis approached significance (P = 0.057). CONCLUSIONS: EHE is a very rare clinical entity. The key to diagnosis is the demonstration of cells containing FVIII-RAg. The histology of the tumor, including nuclear pleomorphism and the mitotic count, are of no value in predicting clinical outcome. High cellularity most likely is the most significant parameter predicting an unfavorable prognosis in EHE because mitotic counts often are quite low in both low grade and aggressive tumors. Further studies are needed to identify the factors responsible for the apparent dissociation between the clinical behavior and biologic characteristics of this tumor.
Adolescent↗
Ferrous sulfate toxicity: a review of autopsy findings.
Ferrous sulfate is the leading cause of accidental pediatric poisonings. Despite the requirement for child-resistant packaging for any oral iron product with 250 mg or more per container, the incidence has continued to increase. Although the clinical presentation of iron toxicity has been well described, pathologic findings in human tissue and correlation with clinical data are scant. We reviewed autopsies from the Armed Forces Institute of Pathology of 11 children who died from ferrous sulfate toxicity. Clinical data, morphologic changes, and iron levels in tissue were evaluated. The children's ages ranged from 11 to 36 mo. Prominent iron deposition in gastric and small intestinal mucosa was associated with necrosis, with some cases demonstrating prominent vascular iron deposition. The clinical courses were rapid and progressed from Stage I to Stage III. These observations were correlated with increased levels of iron in various tissues, as determined by analytical atomic absorption spectrophotometry. The morphologic and chemical analysis data provide information on the pathogenesis of ferrous sulfate poisoning; the vascular iron deposition may be related to subsequent hemorrhage. In the liver the periportal necrosis is probably a direct cytopathic effect of the highest levels of iron carried to these cells by the portal blood flow.
Child, Preschool↗
Ciliated hepatic foregut cyst: a study of six cases and review of the literature.
Ciliated hepatic foregut cyst (CHFC) is a rare, benign, solitary cyst consisting of ciliated pseudostratified columnar epithelium, subepithelial connective tissue, a smooth muscle layer, and an outer fibrous capsule. We studied six previously unreported cases of CHFC and 50 cases from the literature. The literature search revealed that Friedreich first described the lesion in 1857 and hypothesized its congenital origin. The cyst generally is found incidentally on radiologic imaging or during surgical exploration, although one case presented with portal vein compression. It occurs more frequently in men and is found most commonly in the medial segment of the left hepatic lobe, unlike most other solitary cysts that show a female predominance and greater occurrence in the right hepatic lobe. Two of the 56 cases were multilocular. There has been an increase in the number of reports of CHFC during the past 15 years. This may reflect the increased availability and use of various radiologic imaging modalities. A large number of cases have been reported in the Japanese population, but the significance of this is unclear. CHFC should be considered in the differential diagnosis of other solitary liver cysts, including simple cysts, hepatobiliary cystadenomas, and parasitic cysts.
Adenoma, Bile Duct↗
Recurring fibro-obliterative venopathy in liver allografts.
Recurrent diseases in liver allografts are not uncommon. These occur most frequently in those transplanted for viral hepatitis B and C. We report an unusual case of recurrent process in two consecutive liver allografts received by a 37-year-old woman, who previously had an unremarkable past medical history but developed a rapidly progressive cholestatic liver failure. Histopathologic examination of the native liver showed fibroocclusive lesions of both terminal hepatic venules and portal vein branches. The exuberant fibroobliterative process created dense fibrosis with whorled appearance, and broad fibrous septa connecting adjacent central areas, and sometimes bridging portal to central areas. Dense portal fibrosis resulted in compression atrophy and loss of bile ducts. The first allograft, which failed within 3 months, showed histopathologic findings similar to that of the native liver. A liver biopsy that was performed 20 months after the second liver transplant again showed similar histopathology. The histopathologic features and clinical presentation of this patient suggest an unusual form of recurring progressive fibroobliterative venopathy causing liver failure.
Adult↗
Long-term survival of a young woman with peripheral cholangiocarcinoma: a case report.
Cholangiocarcinoma is the second most common primary tumor of the liver after hepatocellular carcinoma and accounts for 5 to 25% of primary hepatic malignancies. Patients with intrahepatic or peripheral cholangiocarcinoma (ICC) most often present at an advanced stage leading to a poor prognosis. A review of the literature has produced only 10 patients who have survived over five years. We review the case of a young woman with a large cholangiocarcinoma, who has been disease free for eight years. The patient was treated with a right hepatic lobectomy, and received 4 cycles of 5-fluorouracil and levamisole postoperatively. Known factors associated with longer survival in patients with ICC include lack of evidence of local invasion (i.e. capsular, lymphatic, or vascular), negative margins, mucoblia, and well differentiation of the tumor, as well as the absence of lymph node metastases. Our patient had negative margins and lymph nodes, and showed no local invasion. However, no mucobilia was noted, and the tumor was only moderately differentiated. Young age has never been associated with increased survival. ICC remains a relatively uncommon tumor with an insidious onset and late presentation contributing to poor survival. Surgical resection remains the only therapeutic option. Since few patients are potentially resectable at the time of presentation, efforts at early diagnosis and options for adjuvant therapy are imperative.
Adult↗
Squamous cell carcinoma arising in a ciliated hepatic foregut cyst.
Ciliated hepatic foregut cysts are rare congenital lesions derived from the embryologic foregut. They are considered benign, and a review of 64 published cases revealed no instances of malignant transformation. We report a case of squamous cell carcinoma arising in a ciliated hepatic foregut cyst in a 51-year-old man. The tumor was found during a routine cholecystectomy and involved the adjacent mesentery and duodenal wall. There was histologic evidence of perineural and perivascular involvement. Despite an en bloc resection of the tumor and contiguous areas of gross involvement, the patient died 2 months later. Although aspiration of cyst contents is an accepted treatment for asymptomatic lesions, this case suggests that most ciliated hepatic foregut cysts should be excised, especially when radiologic studies yield equivocal results.
Carcinoma, Squamous Cell↗
Liver involvement in Langerhans' cell histiocytosis: a study of nine cases.
Nine cases of Langerhans' cell histiocytosis (LCH) of the liver are presented. Five of the patients had liver involvement only. Other organ systems, notably the lymph nodes and skin, were involved in the other four patients. Four of the patients had sclerosing biliary disease with infiltration of the bile ducts by Langerhans' cells, whereas in two other patients, the biliary sclerosis was not associated with direct hepatic involvement by Langerhans' cells. Histologically, the lesions were composed of focal aggregates of Langerhans' cells in a polymorphous background of mature eosinophils, lymphocytes, neutrophils, and plasma cells. LCH encompasses a syndrome that has a broad range of clinical presentations and that might involve the liver solely as tumor-like lesions or cystic lesions, or as part of systemic disease. Even when Langerhans' cells are not demonstrable, sclerosing cholangitis can be seen in LCH.
Antigens, CD1↗
Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial.
Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin alpha1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers. End-of-treatment biochemical response was seen in 37.1% of patients treated with combination therapy, 16.2% of patients treated with IFN alone, and 2.7% of untreated controls by intent-to-treat analysis (IFN/TA1 vs. IFN, chi2 = 4.05, P = .04). HCV RNA clearance was seen in 37.1% of IFN/TA1-treated patients and 18.9% of IFN-treated subjects. Mean HCV RNA titers were significantly lower than baseline at weeks 8, 16, and 24 after drug initiation among patients treated with IFN/TA1 but not in the other treatment arms. Histological improvement, as evidenced by a decrease in HAI of more than two points, occurred in the combination therapy arm more frequently than in comparison groups. Cumulative sustained biochemical responses were 14.2% and 8.1% in the IFN/TA1 and IFN arms, respectively, based on an intention-to-treat model. The combination of TA1 and standard IFN treatment for chronic hepatitis C showed evidence of biological activity at the completion of treatment by biochemical, histological, and virological outcome measures. Further research involving longer duration and varied dosing is needed.
Adult↗
Sarcoidosis of the liver and bile ducts.
In sarcoidosis, granulomas are frequently present in multiple organs, including the liver. Typically, epithelioid granulomas (noncaseating) are scattered throughout the liver, but confluent granulomas can be present in cases with severe hepatic involvement. The characteristic inclusions in giant cells (for example, Schaumann bodies and asteroid bodies) are not seen in all cases and are not pathognomonic. The granulomas of sarcoidosis may heal without a trace, but confluent granulomas can result in extensive, irregular scarring. Occlusion of intrahepatic portal vein branches by the granulomatous inflammation probably accounts for the development of portal hypertension in some cases. A granulomatous cholangitis leading to ductopenia seems to be the underlying pathogenetic mechanism of the chronic cholestatic syndrome of sarcoidosis. Recognition of this syndrome is important in the differential diagnosis of other chronic cholestatic diseases, such as primary biliary cirrhosis or primary sclerosing cholangitis. Other rare complications of sarcoidosis are the Budd-Chiari syndrome and obstructive jaundice attributable to hepatic hilar lymphadenopathy or strictures of the bile ducts.
Bile Duct Diseases↗
Solitary fibrous tumor of the liver: a clinicopathologic and immunohistochemical study of nine cases.
Nine cases of primary solitary fibrous tumors of the liver are presented. The patients are 7 women and 2 men between the ages of 32 and 83 years (mean, 57.5 years). Clinically, palpable masses were detected during physical examination in five patients. Two patients presented with symptoms of cholecystitis, one with hematuria, one with periumbilical pain, and one with hypoglycemia. One patient was found to have an abdominal mass during follow-up evaluation for colonic carcinoma, whereas in one patient the tumor was an incidental finding at autopsy. Two patients were asymptomatic, and the tumor masses were detected during a routine physical examination. Grossly, the tumors varied in size from 2 to more than 20 cm in greatest dimension and were described as firm, white-to-gray, well or ill defined. Eight tumors were described as intraparenchymal lesions, two were grossly necrotic, and one tumor was attached by a pedicle to the liver capsule without infiltration into the liver parenchyma. Histologically, most of the tumors had a bland appearance with the classic short storiform (so-called patternless) pattern and absence of cellular atypia, mitoses and/or necrosis. However, in two cases, there was marked cellular atypia and mitotic figures varying from 2 to 4 mitoses per 10 high power field (hpf). Immunohistochemically, all the tumors showed a strong positive reaction against antibodies for CD-34 and vimentin. Follow-up information showed that two patients died within days of postsurgical resection of the tumor, whereas one was alive and well 1 year after initial diagnosis. No follow-up information was available for the other five patients. The cases herein presented highlight the ubiquitous distribution of this neoplasm and the similar clinical and histopathological features to those observed in serosal surfaces. Solitary fibrous tumors of the liver, although rare, need to be considered in the differential diagnosis of mesenchymal lesions of the liver.
Adult↗