College of American Pathologists

2012 — December Case of the Month

Posted December 14, 2012


CAP Foundation Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 78-year-old woman with a history of hepatitis C and liver mass underwent a lobectomy, which was remarkable for a 12.0 cm, focally necrotic, yellow/green variegated mass. The margins of resection including diaphragm were free of tumor. The tumor was positive for HepPar-1 and a-fetoprotein (AFP) and negative for chromogranin, synaptophysin, HMB-45 and Leu-M1.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 40, and is moderately differentiated hepatocellular carcinoma (grade 2).

Criteria for Diagnosis and Comments:
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy in adults. Multiple risk factors can contribute to the development of this neoplastic process, such as viral hepatitis infection with HBV or HCV, cirrhosis (independently of cause), exposure to aflatoxin, use of anabolic steroids and tyrosemia. The patient is usually asymptomatic during early stage disease and may present with symptoms and signs of advanced disease, such as abdominal pain, weight loss, hepatomegaly, ascites and jaundice.

Grossly, HCC can be either a single nodule or multinodular. Hemorrhage and necrosis are frequently present in the tumor. Microscopically, HCC commonly has a trabecular growth pattern with more than three hepatocytes per plate with abundant eosinophilic cytoplasm, increased nuclear atypia, a high nuclear/cytoplasmic ratio and prominent nucleoli. These cords of cells are lined by endothelial cells and separated by vascular sinusoids. The reticulin framework is disrupted and usually absent. Less frequently, HCC may have an acinar or pseudoglandular pattern, which can result from bile production by tumor cells and secretion into dilated canaliculi between the cells, or from central necrosis of tumor cords. Cytoplasmic inclusions, such as Mallory bodies and hyaline globules can also be present in tumor cells. The majority of the HCC cases will have underlying cirrhosis. Well-differentiated carcinomas will mimic the growth pattern of normal cells with preservation of the reticulin framework. Moderately-differentiated HCC usually assumes a trabecular growth pattern, while poorly-differentiated HCC has a more compact/solid growth pattern. The tumor cells do not generate a desmoplastic reaction within the hepatic stroma as compared to epithelial neoplasms. The histologic grading of HCC consists of four categories which measure the degree of hyperchromasia, nuclear atypia, the nuclear/cytoplasmic ratio and overall architecture. Grade I HCC is a well-differentiated tumor with low nuclear atypia and minimal architecture disruption, while grade IV HCC has marked pleomorphism and giant cells infiltrates. Tumors with high nuclear grade and vascular invasion have a poor prognosis. The tumor staging relies on tumor size, number of nodules and the presence of vascular invasion, as well as adjacent organ invasion.

The differential diagnosis of HCC includes other hepatic lesions, such as focal nodular hyperplasia, angiomyolipoma, metastatic pancreatic or small bowel neuroendocrine tumors, and renal cell carcinoma.

Cytokeratin 8 and 18 and HepPar-1 are useful markers to identify cells of hepatic origin. AFP immunostainings can highlight HCC tumor cells in some cases. Compared to focal nodular hyperplasia and other benign hepatic lesions such as hepatic adenoma, HCC has hepatocyte plate thickness of more than three cells, a high nuclear/cytoplasmic ratio, as well as increased nuclear atypia. The trabecular growth pattern and pseudogland formation can also help to differentiate HCC from benign lesions.

Hepatic angiomyolipomas with epithelioid smooth muscle cell proliferation can mimic HCC tumor cells. These are perivascular epithelioid cell tumors (PEComas) and therefore can be associated with tuberous sclerosis. Immunostains for smooth muscle actin, desmin, HMB-45 and CD117 are positive in the smooth muscle cells and can help distinguish these two lesions. HMB-45 is an important differentiation marker, since no primary hepatic lesion is positive for this stain.

Focal nodular hyperplasia (FNH) is a malformation and consists of hepatocytic hyperplastic nodules that are separated by fibrous septae and this gives this entity the characteristic central stellate scar. The other entity in liver that may have a central scar is HCC, fibrolamellar type. FNH is most commonly found in adult women and there is a frequent association with hepatic hemangiomas. These contain numerous vessels. The hepatocytic component consists of hepatocytes arranged in a 2-cell thick plate and supported by reticulin network.

Large tumor cells with abundant eosinophilic or clear cytoplasm present in neuroendocrine tumors and renal cell carcinoma can appear similar to poorly differentiated HCC cells. Neuroendocrine markers, such as chromogranin and synaptophysin and renal carcinoma markers, such as Leu-M1 and RCC antigen, can aid in the diagnosis of these lesions.

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. What is the most common primary hepatic tumor in adults? A. Angiomyolipoma
B. Focal nodular hyperplasia
C. Hepatocellular carcinoma
D. Metastatic renal cell carcinoma
E. Neuroendocrine tumor
2. Which tumor can cause an increase in serum α-fetoprotein? A. Angiomyolipoma
B. Focal nodular hyperplasia
C. Hepatocellular carcinoma
D. Metastatic renal cell carcinoma
E. Neuroendocrine tumor
3. Which tumor is characterized by HMB-45 positivity? A. Angiomyolipoma
B. Focal nodular hyperplasia
C. Hepatocellular carcinoma
D. Metastatic renal cell carcinoma
E. Neuroendocrine tumor


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  3. Murakata LA, Ishak KG, Nzeako UC. Clear cell carcinoma of the liver: A comparative immunohistochemical study with renal clear cell carcinoma. Mod Pathol. 2000;13:874-881.
  4. Petrolla AA, Xin W. Hepatic angiomyolipoma. Arch Pathol Lab Med. 2008;132:1679-1682.
  5. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet. 1999;353:1253-1257.

Paul M. Rodriguez-Waitkus, MD
Houston, TX

Talat M. Nazir, MD, DO FCAP
Surgical Pathology Committee
Houston, TX