Tumors In The Liver - Diagnostic Problems
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
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)
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
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.
- 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|
|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|