Case 2 -

Hepatocellular Adenoma (HA) Linda D. Ferrell, M.D. Wendy L. Frankel, M.D.

Clinical history and operative findings: 30 year old woman with chest pain and RUQ pain for 6-9 months. Abdominal U/S demonstrated a liver mass that was confirmed with abdominal CT and MRI. The tumor was 8 cm and hemorrhagic while the adjacent liver appeared normal. Case 2 - Figure 1 - Hepatocellular proliferation with areas containing fibrin and hemorrhage, low power Case 2 - Figure 2 - Bland hepatocytes and vessels with no bile ducts, medium power Case 2 - Figure 3 - Bland hepatocytes and thin walled vessel with no bile ducts, high power Case 2 - Figure 4 - Hepatocytes arranged in two-cell-think liver plates with intact reticulin Framework, H&E and reticulin stains, medium power Pathologic findings: The tumor was hemorrhagic and tan with a smooth cut surface. Sections show a proliferation of hepatocytes with areas containing fibrin and hemorrhage. No portal areas are seen, but there are thin walled vessels. The hepatocytes are arranged in two-cell-thick liver plates with intact reticulin framework. Diagnosis- Hepatocellular Adenoma (HA) Comment Clinical features. Hepatic adenomas (HA) are rare tumors that are seen almost exclusively in young women during their reproductive years and are only rarely found in men or children. HA can be single or multifocal; the latter condition known as multiple hepatocellular adenomatosis. These tumors occur in a liver that is histologically normal or nearly normal. The clinical presentation is generally that of an abdominal mass, but some patients also have complaints of abdominal pain, discomfort, or nausea, and a significant number present with hemoperitoneum. Serum alkaline phosphatase may be elevated, but serum AFP levels are generally normal or minimally elevated. Radiographically, the lesions show an increased vascular pattern. Pathogenetic features. Many HAs are thought to result from the use of oral contraceptives or anabolic steroids. However, with the low-dose pills now widely used, the incidence may be decreasing. Some of the HAs associated with oral contraceptives appear to regress after cessation of the drugs, but others do not. Other risk factors for the development of adenomas include metabolic disorders, especially the carbohydrate metabolic disorders such as the glycogen storage diseases I and IV, galactosemia, and familial diabetes mellitus, as well as tyrosinemia. The consensus opinion of the International Working Party is that the diagnosis of adenoma should not be made for a lesion arising in a cirrhotic liver unless there is evidence of regression when the stimulus is removed or one of the above risk factors is present. Rarely, hepatocellular carcinomas have been found arising within HA. Gross features. HAs are round tumors that tend to bulge on cut section, are soft, and are typically somewhat lighter in color than the surrounding liver, but the appearance may vary if necrosis or hemorrhage are present. HA generally lacks significant evidence of fibrosis or nodularity, but rarely, such features may be present. Usually, a capsule is not present. Rarely, adenoma may have a slate gray to black color due to the presence of large amounts of lipofuscin pigment, the so-called "black adenoma". Microscopic features. HAs are composed of a relatively uniform population of hepatocytes arranged in cell plates which are one to three cells thick. The cell plates are usually more irregular and nonlinear than in the normal liver. A key feature is that the reticulin framework of the cell plates is intact or only focally decreased. The tumor cells are usually about the same size as in the normal liver, but they can also be slightly smaller or larger compared to normal hepatocytes. Even if the size of the cells vary, however, the nuclear:cytoplasmic ratio remains about the same as in normal liver. The cytoplasm of the tumor cells may be eosinophilic, clear, or contain fat droplets, and bile stasis, lipofuscin pigment, or Mallory hyaline may be noted. Other variations in cellular morphology such as multinucleated hepatocytic tumor cells and focally atypical or pleomorphic hepatocytes may also be present. Regardless of the cellular morphology, mitotic figures are absent or extremely rare. Variations in the architecture such as the formation of acini (pseudoglands, or gland-like structures composed of hepatocytes) are relatively common findings; such acinar structures can contain bile. Alterations in the sinusoids can also be present; they may appear compressed, resulting in a somewhat uniform, solid appearance to the tumor, or alternatively, sinusoidal dilation and peliosis hepatis may be present. Large vessels are often quite prominent. Kupffer cells may be seen but tend to be fewer in number than in the normal liver. HAs may or may not be encapsulated, and if a capsule is present, it is often only partially complete, with foci of tumor cells merging with the adjacent parenchyma at sites where the capsule is absent. Adenomas associated with anabolic steroids are more likely to show nuclear atypia, peliosis hepatitis, or a prominent acinar (pseudoglandular) pattern. No portal zones are present. Areas of infarction and hemorrhage are relatively frequent findings. Special studies. HA will stain positively for the usual hepatocellular markers including the cytokeratin marker CAM5.2 and the canalicular marker polyclonal CEA. As will often show CD34 positivity on the endothelial cells lining the cell plates, similar to that seen in hepatocellular carcinoma, so this marker cannot be used to distinguish the two lesions. Alpha-fetoprotein is negative in these lesions. Differential diagnosis. Diagnostic problems most often arise in the differentiation of HA from FNH (Table 2) or well-differentiated hepatocellular carcinoma (HCC) (Table 3). For HA, the relatively uniform cell population resembling normal liver and lacking mitotic activity, lack of cell plates greater than three cells thick, and an intact reticulin framework lining the cell plates help to distinguish the lesion from well-differentiated HCC. For differentiation from focal nodular hyperplasia, the lack of nodularity, fibrous bands or central fibrous zone, and proliferating bile ductules are the most helpful features. However, one must be careful not to confuse acinar formation seen in HA for bile ductules. The distinction among these lesions may be difficult, especially on small samples. Immunohistochemistry does not appear to be helpful in distinguishing HA from either of these two lesions. References Ferrell L: Hepatocellular carcinoma arising in a focus of multilobular adenoma. American Journal of Surgical Pathology 17:525-529, 1993. Hytiroglou P, Theise N: Differential diagnosis of hepatocellular nodular lesions. Sem Diag Pathol 15:285-299, 1998. Ishak K, Rabin L: Benign tumors of the liver. Medical Clinics of North America 59:995-1013, 1975. Kong C, Appenzeller M, Ferrell L: Utility of CD34 reactivity in evaluating focal nodular hepatocellular lesions sampled by fine needle aspiration biopsy. Acta Cytologica 44:218-222, 2000. Nguyen B, Flejou J, Terris B, et al: Focal nodular hyperplasia of the liver: A comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Amer J Surg Pathol 23:1441-1454, 1999. Tao L: Oral contraceptive-associated liver cell adenoma and hepatocellular carcinoma: Cytomorphology and mechanism of malignant transformation. Cancer 68:341-347, 1991. Wanless I, Mawdsley C, Adams R: On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 5:1194-1200, 1985. Wheeler D, Edmondson H, Reynolds T: Spontaneous liver cell adenoma in children. American Journal of Clinical Pathology 85:6-12, 1986. Nodules in a Non-Cirrhotic Liver   Adenoma Focal Nodular Hyperplasia Nodular Regenerative Hyperplasia Clinical 3rd-4th decade, OCP, usually women, acute abdominal pain 3rd-4th decade, some OCP, women > men asymptomatic 5th-7th decade, women=men, portal hypertension, connective tissue disorder Gross Usually single, tan-hemorrhagic Usually single, tan nodular Multiple, tan Hepatocytes Usually normal, cytoplasmic glycogen or fat may be present Usually normal, cytoplasmic glycogen or fat may be present Usually normal Architecture 1-2 cells wide, reticulin normal 1-2 cells wide, but wider may be present, plates can be compressed to give impression of solid growth 1-2 cells wide, reticulin intact Bile ducts None present Present in fibrovascular zone, edge of hepatocytic nodules Portal tracts present Vessels Peliosis hepatis and sinusoidal dilation can be seen; some large vessels, intranodular arteries common Abnormal large muscular vessels generally surrounded by a zone of connective tissue stroma Rare intranodular arteries (nontriadal) Connective tissue Occasional fibrous septa, encapsulation discontinuous Fibrovascular central zone, not encapsulated, chronic inflammatory infiltrates may be present. Compressed parenchyma and regenerative nodules without fibrosis