Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

This study examined clinico-histopathologic differences between North American patients who developed hepatocellular carcinoma with and without cirrhosis.Histologic slides and clinical records of cases were reviewed. Cases were classified according to defined histopathologic criteria. Analyses were performed using appropriate tests.A total of 42.6% of cases were noncirrhotic. The trabecular type of hepatocellular carcinoma was the most common growth pattern in both groups. Patients with cirrhosis were significantly older, had high grade tumors, and local portal venous invasion significantly more often than patients without cirrhosis. Encapsulated tumors occurred in significantly more in patients without cirrhosis. Patients without cirrhosis survived longer than patients with cirrhosis {P -c.OOOl) and had a better 5-year survival experience. On average, in patients with cirrhosis, serum aspartate transaminase and total serum bilirubin were significantly greater, and serum albumin was significantly lower.In general, hepatocellular carcinoma in North American patients with cirrhosis tended to be less well differentiated than those found among patients without cirrhosis. The pathology, natural history, and prognosis of this tumor is significantly influenced by the presence or absence of cirrhosis in the nonneoplastic liver, and the presence of cirrhosis portends a poorer prognosis.

Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptormediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-␣, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells.

Abdominal involvement in angioedema is often a challenge to diagnose. Acute onset abdominal pain is its most common presenting symptom, and misdiagnosis may lead to unnecessary surgical intervention. Familiarity with the types and presentations of angioedema can be invaluable to clinicians as they consider the differential diagnoses of a patient presenting with abdominal pain. Detailed personal and family histories, careful physical examination of the patient, combined with knowledge of angioedema types, can help clinicians perform their diagnostic evaluation. An accurate diagnosis is essential in order to provide appropriate treatment to patients with angioedema. Depending upon the diagnosis, treatment may be the avoidance of provoking factors (such as allergens or medications), inhibiting histamine-provoked reactions, or treating C1 esterase inhibitor deficiency.

MATERIALS AND METHODSThe files of the Armed Forces Institute of Pathology, Washington DC, were searched for clear cell tumors of liver and kidney. Ten examples of each tumor were selected if the tumor was unequivocally primary in that organ, and if the paraffin block was available with sufficient tissue for recuts. Also, 11 clear cell tumors from other organs, three salivary gland (one mucoepidermal carcinoma, clear cell type; two clear cell adenocarcinomas), three lung (three poorly differentiated squamous cell carcinomas with clear cell features), two thyroid gland (two follicular carcinomas with clear cells), two ovary (two clear cell carcinomas), and one urinary bladder (one transitional cell carcinoma with clear cell features) were retrieved using the same criteria.

Background. The finding of an association between one primary tumor and others is an area of continuing interest from clinical and pathologic viewpoints. The authors studied patients in North American with hepatocellular carcinoma associated with extrahepatic primary malignancies (EHPMs) and compared them with patients who had hepatocellular carcinomas not associated with other neoplasms. The authors know of only four other series that have investigated such cases, none of which was from North America. Methods. The authors retrospectively reviewed 1349 consecutive cases of histologically diagnosed hepatocellular carcinoma (HCC) at the Armed Forces Institute of Pathology over a 14‐year period. Seventy‐four patients (5.5%) had an EHPM, and these were compared with the 1275 patients who did not have another primary malignancy. Statistical comparisons were made using the chisquare statistical or Fisher's exact test, as appropriate, and life‐table survival analyses were performed. Results. Significantly more men (P = 0.02) than women had EHPMs, and their mean age of 69.2 ± 2.1 years was significantly older (P < 0.05) than that of those without EHPMs (59.9 ± 1.0 years). Seventeen (19.8%) EHPMs occurred before HCC, 66 (76.7%) occurred synchronously, and 3 (3.5%) occurred metachronously. The probability of finding an EHPM increased if the nonneoplastic liver was cirrhotic or dysplastic. Mean survival for the HCC with EHPM group did not differ significantly from that for the group without EHPM. Conclusions. Extrahepatic primary malignancies do not significantly influence the survival of patients with HCC. The most common EHPMs associated with HCC are either diseases of old age or those already known to be common among North American populations.

Background. Several of the large studies addressing prognosis and survival from hepatocellular carcinoma (HCC) have been from Europe and Asia, but only a few have emanated from North America. Survival statistics from other parts of the world may not be applicable to the North American population because of etiologic, demographic, cultural, lifestyle, and intangible differences. The current study investigated the survival experience and histologic correlates of North American patients with HCC and compared findings with similar studies from North America and other parts of the world. Methods. One thousand sixty‐three patients examined during a 14‐year period, met inclusion criteria for this study. Each patient was placed in one of three categories based on the duration of survival from date of diagnosis of HCC. Each tumor was examined histologically and classified according to World Health Organization criteria. Patient's sex and age at diagnosis were obtained from case records. Survival analyses and comparisons were performed using appropriate methods. Variables were tested for association using chi‐square tests and randomization tests as appropriate. Results. Age, sex, tumor growth pattern, Edmondson and Steiner's nuclear grades, mitotic index, and presence or absence of tumor giant cells or portal venous invasion, were found to have statistically significant (P < 0.05) relationships with the duration of patient survival. Significantly better survival was found to be associated with female sex, low nuclear grade, low mitotic index, age at diagnosis younger than 50 years, absence of giant cells, and absence of portal venous invasion. Conclusions. Certain histopathologic features of HCC may be useful for predicting patient survival and, thus, for empiric prognostication of these patients. Cancer 1995; 76:579–88.

Angioedema is a constellation of syndromes that present a great challenge to the clinician. The term "angioedema" describes the localized, transient, episodic edema of the deeper layers of the skin or of the mucosa of the gastrointestinal tract. Although angioedema may affect any part of the body, the skin and gastrointestinal tract are involved most commonly by far. Episodic abdominal pain arising from angioedema affecting any intra-abdominal organ may occur without skin angioedema; therefore, angioedema must be included in the differential diagnosis of intermittent, unexplained abdominal pain. Angioedema is caused by extravasation of plasma in the affected areas, which at times is accompanied by nonspecific, minimal cellular infiltrate. The most commonly identified causes of angioedema are medications, allergens, and physical agents, but most angioedema is idiopathic. Rare forms of angioedema associated with either hereditary or acquired faulty activation of the complement and kallikrein-kinin systems have been extensively described. Taking a comprehensive personal and family history, performing a physical examination, and compulsively monitoring the response to therapy are the most rewarding and cost-effective diagnostic and treatment tools. Diligent and knowledgeable follow-up by the attending physician spares patients costly and unnecessary tests as well as harmful treatment. The most effective treatment depends on the identification of the causative mechanism and--especially when the mechanism is not identified--on the clinician's knowledge and experience with innovative therapeutic regimens.