Kamal G. Ishak

Histological grading and staging of chronic hepatitis

‘Armed Forces instifute of Pathology, Washington, USA, 2University of Lisbon. Lisbon, Portugal, -‘Hofstetten, Switzerland, 4Servizio di Anatomia e Istologia Patologica. Spedali Civili, Brescia, Italy, 5Department of Medicine, University of Leuven, Leaven, Belgium, 61nstitute for Pathology, University of Basel, Basel, Switzerland, 7Department of Pathology, University of Graz. Graz, Austria, 8Department of Pathology, University of Leuven, Leuven, Belgium. 9 Weiden, Germany, ‘ODepartment of Pathology, Western Infirmary, University of Glasgow, Glasgow, UK, “Department of Pathology, ~osp~talfor Sick Children, University of Toronto, Toronto, Canada, ~‘~nstitute of Liver Studies, King’s College Hospital, London, UK, 13Frederiksberg, Denmark, Is Watt, Switzerland, “Vienna, Austria

Benign Tumors of the Liver

Benign tumors of the liver are fairly rare. Some occur in all age groups and both sexes while others are concentrated in 1 age group or 1 sex. Most benign tumors are diagnosed by exploratory laparotomy prior to treatment of other conditions. Due to the danger of life-threatening complications e.g. internal bleeding due to rupture laparotomy and open biopsy of suspected tumors and surgical resection where necessary should not be delayed. The etiology and pathogenesis of benign liver tumors are unknown. Multiparity pregnancy and estrogen therapy have been shown to be associated with hepatocellular adenoma. The following types of benign liver tumor are discussed as to incidence treatment and outcome and photographed: 1) tumors of hepatocellular origin; 2) tumors of cholangiocellular origin; 3) tumors of fibrous tissue; 4) tumors of adipose tissue; 5) tumors of muscle tissue; 6) tumors of blood vessels; 7) tumors of lymph vessels; 8) tumors of mesothelial tissues; and 9) tumors and tumor-like lesions.

Isoniazid Liver Injury: Clinical Spectrum, Pathology, and Probable Pathogenesis

The clinical spectrum of isoniazid-induced liver injury seems to be clinically, biochemically, and histologically indistinguishable from viral hepatitis, except that the injury occurs primarily in persons older than 35 years. A possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug has been found. Examination of isoniazid metabolites showed that patients with rapid acetylator phenotype hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. It seems likely that formation of chemically reactive metabolites is also the biochemical event initiating isoniazid liver injury in man. Recognition of the seriousness of isoniazid hepatic injury, not readily accepted at first, has led to revisions in the uses of isoniazid prophylaxis.

Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients

Fifty-two hepatobiliary cystadenomas and 18 hepatobiliary cystadenocarcinomas were drawn from the files of the Armed Forces Institute of Pathology and Rhode Island Hospital and studied in an attempt to correlate light microscopic features of the tumors with immunohistochemical and follow-up data. The cystadenoma patients ranged in age from 2 to 87 years at the time of initial diagnosis (mean, 45 years). All the cystadenomas were multilocular with benign cuboidal to columnar epithelium, and 44 (85%) had densely cellular spindle cell (“ovarian-like”) stromata; 96% were female. Fifty-one cystadenomas were macrocystic lesions, typically lined by mucinous epithelium; one of the benign lesions was a serous cystadenoma (microcystic adenoma) reminiscent of the more commonly encountered pancreatic lesion of the same name. The cystadenocarcinoma patients ranged in age from 24 to 90 years at the time of first diagnosis (mean, 59 years); eight patients (44%) were male. All but one of the lesions were multilocular with malignant in situ (one case) or invasive tubulopapillary (15 cases), solid (one case), or adenosquamous (one case) epithelial components. Areas of preexisting benign cystadenoma were found in six (33%), an observation suggesting that benign lesions may evolve into malignant ones in some patients. Most cystadenomas and cystadenomas and cystadenocarcinomas arose in the liver, a few in the extrahepatic biliary system (including the gallbladder). On follow-up, the cystadenoma patients in general were successfully treated by surgical excision of the lesions in toto; patients treated by subtotal resection often had persistent symptomatic disease. Four cystadenocarcinoma patients died of their tumors; another two patients were alive with persistent disease at last follow-up. In both the benign and the malignant lesions, most tumor cells were positive on immunohistochemical staining with antibodies to cytokeratin. epithelial membrane antigen, and carcinoembryonic antigen; scattered chromogranin-positive cells also appeared in a few tumors of both types. Immunohistochemistry did not yield a diagnostic immunoprofile to distinguish cystadenoma from cystadenocarcinoma or from other epithelial lesions arising within the abdominal cavity. At least two types of cystadenocarcinoma exist, one developing exclusively in female patients, usually accompanied by an “ovarian-like” stroma, which follows an indolent course:and the other, lacking the distinctive cellular stroma, seen in males, follows a more aggress ve course and is more likely to result in the patients death from tumor. It remains an open question whether the cystadenocarcinomas lacking a mesenchymal stroma, which arise in women, will follow the same aggressive course as similar lesions arising in men.

Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases

The clinical, morphologic, and follow‐up data on 35 patients with hepatoblastoma and 12 patients with hepatocarcinoma have been reviewed and discussed. Differences in the age and sex incidence and in clinical and morphologic findings between the 2 groups of tumors were emphasized. The prognosis in hepatocellular carcinoma occurring in children reported in this series was poor, regardless of the form of therapy. Six of the 35 infants and children with hepatoblastoma, however, are alive and well, with no evidence of recurrence; they have survived for periods of time varying from 5 to 13 years following resection of their neoplasms. On the basis of the findings in this study early exploration, biopsy, and surgical resection are recommended in all patients. The authors consider that the only hope of cure in hepatoblastoma is surgical excision.

Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases.

The clinical, morphologic, and follow-up findings in 32 patients with a hitherto rarely reported tumor of the liver are reported. The study comprised 20 women (62.5 per cent) and 12 men (37.5 per cent) ranging in age from 19 to 86 years (average, 49.65 years). The tumors were discovered incidentally in four patients (12.5 per cent). Four patients (12.5 per cent) had jaundice attributable to the tumors; one of these patients experienced liver failure. One patient presented with an acutely painful abdomen due to hemoperitoneum. The remaining patients had nonspecific complaints. Grossly, the tumors were often multiple and involved both lobes of the liver. They were generally white and firm to hard. Microscopically, the neoplastic cells infiltrated sinusoids and intrahepatic veins of all sizes. Two types of tumor cells were identified--dendritic and epithelioid. Tumor cells were also vasoformative and synthesized Factor VIII-related antigen. Nine patients survived five years or longer. Two of these patients were alive five years, two nine years, one 12 years, and one 15 years after the onset of disease. Three patients died seven, ten, and 28 years, respectively, after the initial diagnosis. This vascular tumor has distinctive morphologic features that allow differentiation from sclerosing carcinoma and angiosarcoma. Although the prognosis is much more favorable than that for angiosarcoma, extrahepatic metastases occurred in nine of the patients (28 per cent) in this series. The biologic behavior of the tumor may be related in part to its matrix, which may show inflammation, dense sclerosis, and calcification.

Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study.

Combined hepatocellular‐cholangiocarcinoma is a rare form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation. In a review of 24 cases of this tumor, three histologic types were encountered. Four cases were Type I or “collision tumors,” apparently a coincidental occurrence of both hepatocellular carcinoma and cholangiocarcinoma in the same patient. Twelve cases were Type II or “transitional tumors,” in which there were areas of intermediate differentiation and an identifiable transition between hepatocellular carcinoma and cholangiocarcinoma. Eight cases were Type III or “fibrolamellar tumors” which resembled the fibrolamellar variant of hepatocellular carcinoma but which also contained mucin‐producing pseudoglands. Type III tumors differ from other combined tumors, occurring at a younger age, in the absence of cirrhosis, and having a slightly longer survival. Immunohistochemical (immunoperoxidase) staining for intracellular antigens showed that alpha‐fetoprotein is a fairly specific, although insensitive, marker of hepatocellular differentiation in primary liver cancers, being present in 50% of typical hepatocellular carcinomas and in hepatocellular areas in 29% of combined tumors, but in no cholangiocarcinomas or cholangiocellular areas of combined tumors. Keratin is a good marker of biliary epithelial differentiation, being found in 90% of cholangiocarcinomas and in 52% of combined hepatocellular cholangiocarcinomas, but in no hepatocellular carcinomas. Alpha‐1‐antitrypsin, fibrinogen, IgG, and carcinoembryonic antigen may be found in both hepatocellular carcinoma, cholangiocarcinoma, and in combined tumors; these antigens are therefore of limited use in differential diagnosis.

Biliary cystadenoma and cystadenocarcinoma. Report of 14 cases and review of the literature

The clinical and pathologic features and long‐term follow‐up of eight patients with biliary cystadenoma and six patients with biliary cystadenocarcinoma are reported and the previous literature is reviewed. All the cystadenomas were in middle‐aged women, but the six cystadenocarcinomas occurred in both male (4) and female (2) patients. The majority of the patients with cystadenoma and half of those with cystadenocarcinoma presented with an abdominal mass. Four of the patients whose cystadenoma was excised are alive and well for periods of time ranging from 2 1/2 to 13 years. Two of the patients with cystadenocarcinoma have survived for three years and for three years and eight months, respectively, after subtotal hepatic lobectomy. Morphologically the cystadenocarcinomas differ from the cystadenomas in that the former have cellular pleomorphism and anaplasia and infiltration of the underlying fribrous stroma; they can invade adjacent viscera and may occasionally metastasize to distant sites. The presence of benign epithelium in most cystadenocarcinomas supports their origin from cystadenoma.

Epithelioid hemangioendothelioma of the liver

Epithelioid hemangioendothelioma (EHE) is a rare neoplasm of vascular origin that occurs in the liver and other organs; its etiology is unknown.

Hepatic Injury Associated With Ketoconazole Therapy: Analysis of 33 Cases

Ketoconazole has only recently been recognized as a cause of hepatic injury, with most reports coming from outside the United States. In order to characterize more fully the U.S. experience, we undertook an analysis of 54 reports of alleged ketoconazole-induced liver injury submitted to the Food and Drug Administration from the time of initial marketing in 1980. Thirty-three reports were considered likely instances of ketoconazole-induced hepatitis. The majority of these cases occurred in women more than 40 yr of age. Jaundice was recorded in 27 individuals after therapy of 11-168 days with an average daily dose of 200 mg. Anorexia, malaise, nausea, and vomiting accompanied liver injury in one-third of cases. No instances of rash or eosinophilia were recorded. Serum transaminase and alkaline phosphatase values were consistent with acute hepatocellular injury in 18 patients, with primarily cholestatic injury in 5 patients, and with a mixed pattern in 9 individuals. Only one death seemed attributable to ketoconazole. In that patient, the drug was continued after the appearance of clinical and biochemical evidence of hepatic injury and massive hepatocellular necrosis was present at autopsy. The incidence of symptomatic, potentially serious hepatic injury appears to be very low, perhaps 1 in 15,000 exposed individuals. The presumed mechanism of injury is metabolic idiosyncrasy, although hypersensitivity has not been completely dismissed in some cases reported in the literature. The incidence of mild, asymptomatic, reversible elevations in serum transaminases occurring in ketoconazole recipients has been estimated to be 5%-10%. Periodic biochemical testing and monitoring for symptoms of hepatitis during ketoconazole therapy is recommended to help prevent the development of serious or fatal hepatic injury.