Autoimmune hepatitis with centrilobular necrosis.

Autoimmune hepatitis (AIH) is usually a chronic portal-based hepatitis with prominent plasma cells. Although necroinflammatory activity throughout the lobule is described, centrilobular necrosis (CN) is only rarely the predominant pattern of injury. Recognition of the possibility of AIH in zone 3 hepatitis will lead to prompt steroid therapy and may avert cirrhosis. We report the clinicopathologic features of 6 cases of AIH with CN. The 3 females and 3 males averaged 48 years of age (range 32-66 years). Four patients had a history of autoimmune disorders. All had elevated transaminases and negative serology for viral hepatitis B and C. One had a history of ethanol use. One patient was taking interferon-beta and 1 patient was taking atorvastatin, but none of the patients was taking medication with a temporal relationship to suggest a drug hypersensitivity hepatitis. All patients had positive antinuclear antibody, anti-smooth muscle antibody, or both, although 1 patient was negative for autoantibodies at initial laboratory testing. Four biopsies showed confluent zone 3 necrosis, whereas two biopsies showed spotty CN. Portal inflammation was relatively mild in all cases. Plasma cells were few to numerous in both zone 3 and portal tracts in four biopsies; they were absent in 2 cases. All patients responded to steroid therapy. Two patients relapsed, and rebiopsy in 1 of them showed CN, bridging necrosis, and an increase in the degree of portal-based hepatitis. Another patient was not treated initially; a second biopsy 35 months after presenting revealed periportal hepatitis as well as CN. The histologic spectrum of AIH should be expanded to include zone 3 hepatitis. As with classic AIH, most patients with CN demonstrate serologic and clinical evidence of autoimmunity. Subsequent biopsies in patients with a centrilobular pattern may show evolution to portal-based hepatitis characteristic of AIH but may also show persistence of the zone 3 hepatitis. Unlike other causes of zone 3 hepatitis, AIH is steroid responsive; therefore, timely diagnosis is important.

Miscellaneous conditions of the appendix.

A variety of miscellaneous conditions affect the appendix, both as incidental findings and as causes of clinical signs and symptoms that often mimic appendicitis. Congenital abnormalities of the appendix are rare; the two most commonly reported are congenital absence and appendiceal duplication. Diverticular disease may be an incidental finding, but when inflamed, can be clinically confused with appendicitis. Endometriosis of the appendix, which usually occurs in the setting of generalized gastrointestinal endometriosis, often presents as acute appendicitis, but may present as intussusception, lower intestinal bleeding, and, particularly during pregnancy, perforation. Peritoneal endosalpingiosis often involves the appendiceal serosa and occasionally the wall but has no clinical manifestations in contrast to endometriosis. Vasculitis may be either isolated to the appendix or part of a systemic vasculitis, most often polyarteritis nodosa. Neural proliferations of the appendix include lesions associated with von Recklinghausen's disease, as well as mucosal and axial neuromas that are theorized to progress to fibrous obliteration of the appendix. Mesenchymal tumors of the appendix are most often of smooth muscle type, usually leiomyoma but rarely leiomyosarcoma; nonmyogenic neoplasms such as gastrointestinal stromal tumor, granular cell tumor, Kaposi's sarcoma, and miscellaneous other curiosities occur rarely. Lymphoma affects the appendix exceptionally; in children, Burkitt lymphoma is most common whereas in adults, large cell lymphomas and low grade B-cell lymphomas predominate. Secondary involvement of the appendix by leukemia has been reported. Secondary involvement of the appendix by carcinomas of the female genital tract, particularly ovary, and diverse other sites are in aggregate common but only rarely a clinical or pathological difficulty. Occasionally, however, appendiceal neoplasia that is secondary from another site may dominate the clinical picture and lead to potential pathologic misdiagnosis as primary appendiceal disease.

Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases.

The classification of appendiceal mucinous tumors is controversial and terminology used for them inconsistent, particularly when they lack overtly malignant features but are associated with extra-appendiceal spread. We reviewed 107 appendiceal mucinous neoplasms and classified them as low-grade appendiceal mucinous neoplasm (LAMN) (n = 88), mucinous adenocarcinomas (MACAs) (n = 16), or discordant (n = 3) based on architectural and cytologic features. LAMNs were characterized by a villous or flat proliferation of mucinous epithelium with low-grade atypia. Thirty-nine tumors were confined to the appendix, but 49 had extra-appendiceal tumor spread, including 39 with peritoneal tumor characterized by mucin pools harboring low-grade mucinous epithelium, usually dissecting in a hyalinized stroma. Eight of the 16 MACAs lacked destructive invasion of the appendiceal wall and eight showed an infiltrative pattern of invasion. Extra-appendiceal tumor spread was present in 12 MACAs (four peritoneum, seven peritoneum and ovaries; one ovaries only). In MACAs with an infiltrative pattern, peritoneal tumor consisted of glands and single cells in a desmoplastic stroma. The peritoneal tumor in the remaining cases consisted of mucin pools that contained mucinous epithelium with high-grade atypia and, in some cases, increased cellularity compared with that seen in peritoneal spread in cases of LAMN. Three cases were classified as discordant because the appendiceal tumors were LAMNs but the peritoneal tumors were high-grade. Follow-up was available for 49 LAMNs, 15 MACAs, and 2 discordant cases. None of the patients with LAMNs confined to the appendix experienced recurrence (median follow-up 6 years). LAMNs with extra-appendiceal spread were associated with 3-, 5-, and 10-year survival rates of 100%, 86%, and 45%, respectively. Patients with MACA had 3- and 5-year survival rates of 90% and 44%, respectively (p = 0.04). The bulk of peritoneal disease correlated with prognosis among patients with MACA (p = 0.04) and, to a lesser degree, among patients with LAMNs (p = 0.07). We conclude that: 1) appendiceal mucinous neoplasms can be classified as either low-grade mucinous neoplasms or mucinous adenocarcinoma based on architectural and cytologic features; 2) tumors that can be confidently placed in the low-grade group (which requires rigorous pathologic evaluation of the appendix) and are confined to the appendix are clinically benign in our experience to date; 3) low-grade tumors confined to the appendix are morphologically identical to those with extra-appendiceal spread (except for the usual identification of breach of the wall in the latter cases) and the same designation is appropriate for the appendiceal neoplasia in each situation; 4) the long-term outlook for patients with low-grade tumors and peritoneal spread is guarded with just over half dying of disease after 10 years; 5) appendiceal mucinous tumors with destructive invasion of the appendiceal wall, complex epithelial proliferations, or high-grade nuclear atypia generally pursue an aggressive clinical course and should be classified as mucinous adenocarcinomas; 6) peritoneal tumor can be classified as involvement by LAMN or MACA, and this distinction is of prognostic significance; 7) bulky peritoneal tumor worsens prognosis; and 8) LAMNs associated with high-grade peritoneal tumor behave as adenocarcinoma.

Rapidly progressive fibrosing cholestatic hepatitis--hepatitis C virus in HIV coinfection.

Fibrosing cholestatic hepatitis (FCH) is a severe and progressive form of liver dysfunction seen in organ transplant recipients infected with hepatitis B virus or hepatitis C virus (HCV) and has been attributed to cytopathic liver injury. To date, no case of FCH due to HCV has been reported in HIV-positive individuals. We describe two cases of HCV-induced FCH in two patients coinfected with HIV, culminating in rapidly progressive liver failure and death. Histological features and progression in both cases were not consistent with drug effect or obstruction. Late institution of interferon-based therapy was ultimately unsuccessful. The HCV RNA was not markedly elevated in these cases, suggesting that the cytopathic effect of HCV in these patients was not simply a consequence of viral load. FCH may in part explain the accelerated development of cirrhosis previously observed among coinfected patients. Clinicians should remain vigilant for FCH in the HIV/HCV population and consider antiviral treatment in this setting.