Faculty Bibliography

Precancerous lesions that may be detected in chronically diseased, usually cirrhotic livers, include: clusters of hepatocytes with atypia and increased proliferative rate (dysplastic foci) that usually represent an incidental finding in biopsy or resection specimens; and grossly evident lesions (dysplastic nodules) that may be detected on radiologic examination. There are two types of small hepatocellular carcinoma (HCC) (defined as HCC that measures less than 2 cm): early HCC, which is well-differentiated and has indistinct margins; and distinctly nodular small HCC, which is well- or moderately differentiated, and is usually surrounded by a fibrous capsule. Precise diagnosis of precancerous and early cancerous lesions by imaging methods is often difficult or impossible. Detection of a dysplastic lesion in a biopsy specimen is a marker of increased risk for HCC development, and warrants increased surveillance. High-grade dysplastic nodules and small HCCs should be treated by local ablation, surgical resection, or liver transplantation.

Bone marrow cells have the capacity to contribute to distant organs. We show that marrow also contributes to epithelial neoplasias of the small bowel, colon, and lung, but not the skin. In particular, epithelial neoplasias found in patients after hematopoietic cell transplantations demonstrate that human marrow incorporates into neoplasias by adopting the phenotype of the surrounding neoplastic environment. To more rigorously evaluate marrow contribution to epithelial cancer, we employed mouse models of intestinal and lung neoplasias, which revealed specifically that the hematopoietic stem cell and its progeny incorporate within cancer. Furthermore, this marrow involvement in epithelial cancer does not appear to occur by induction of stable fusion. Whereas previous claims have been made that marrow can serve as a direct source of epithelial neoplasia, our results indicate a more cautionary note, that marrow contributes to cancer as a means of developmental mimicry. Disclosure of Potential Conflicts of Interest is found at the end of this article.

Fibrin ring granulomas are rare lesions whose pathophysiology has remained somewhat elusive. It has been suggested that these peculiar lesions are related to focal vasculitis with endothelial injury and deposition of immune complexes. Fibrin ring granulomas have been described in Q fever; in viral infections such as cytomegalovirus, Epstein-Barr virus, and hepatitis A virus; and in other conditions. We submit the first reported case of fibrin ring granuloma in a patient with chronic hepatitis C infection, in whom other potential etiologies have been excluded, and offer a brief review of available literature on the pathogenesis of both conditions.

BACKGROUND: Stromal invasion is 1 of the main features used to distinguish high-grade dysplastic nodules (DNs) from well-differentiated hepatocellular carcinomas (HCCs). The authors hypothesized that ductular reaction (DR) takes place around noninvasive hepatocellular nodules but not within the stroma contiguous to invasive HCC. METHODS: DR/cytokeratin 7 (CK7)-positive patterns were evaluated in 105 resected small hepatic nodules according to the level of invasion. The nodules were classified histologically prior to immunostaining as noninvasive (large regenerative nodules, low-grade DNs, and high-grade DNs), minimally invasive (early HCCs with a vaguely nodular type), and overtly invasive (typical HCCs with a distinctly nodular type) in a review by expert pathologists, the current gold standard. Intranodular DR (inner DR) and DR around the nodule periphery (outer DR) were assessed separately on a semiquantitative scale from 0 to 4+. RESULTS: DR was 3 or 4+ in the majority of noninvasive nodules (inner DR, 81%; outer DR, 91%), whereas DR was 0 or 1+ in overtly invasive HCCs (inner DR, 96%; outer DR, 81%). Minimally invasive HCCs showed an intermediate DR pattern (2 or 3+ inner DR, 75%; 2+ outer DR, 67%). DR characteristically was absent at the stromal-invasive, leading edge of tumor cells in both minimally invasive HCCs (focal loss of DR/CK7) and overtly invasive HCCs (diffuse loss of DR/CK7). The DR patterns in 41 needle-biopsy samples were similar to the patterns observed in resected nodules. CONCLUSIONS: DR/CK7 immunostaining may help to identify small foci of invasion and to distinguish noninvasive, high-grade DNs from both minimally invasive and overtly invasive HCCs.

The terminology for assessment of chronic viral hepatitis in liver biopsy specimens has become confusing with the proliferation of grading and staging schemes that have paralleled the rise of the hepatitis C epidemic and the importance of mixed viral infections. This review represents a personal approach to the interpretation of these biopsy specimens, aiming at clarifying and simplifying the important points for the general pathologist confronted by these diagnostic dilemmas. The most commonly used schemes-Ishak modification of the Knodell 'hepatic activity index', Scheuer, Metavir, Batts-Ludwig classifications-are presented with evaluation of their pros and cons. Which scheme is selected is less important than the consistent use of a single scheme and the clear naming of that scheme in pathology reports. The importance and clinical implications of identifying severe necroinflammatory activity in the form of 'confluent necrosis' is discussed. Pathologists must also be clear about assessing concomitant diseases, in particular, alcoholic or non-alcoholic fatty liver disease, and be aware that grading/staging schemes for chronic hepatitis do not apply to mixed disease conditions. Other important features to be evaluated in all chronic hepatitis biopsy specimens include iron (which may represent hereditary hemochromatosis or secondary uptake) and neoplasia-associated changes, namely large cell change and small cell change; these findings and their clinical import are updated and reviewed. Sample approaches to composing useful diagnostic reports are also presented.