Hepatic Abscess

Hepatic abscesses can be bacterial, fungal, or amebic, the last principally due to Entamoeba histolytica. Bacterial abscesses result from ascending cholangitis and sepsis. The most common organisms are streptococci, staphylococci, and enteric bacteria. Fungal abscesses are most common in immunocompromised patients. Candida species are the most common pathogens.

Amebic abscesses are rare in the United States but common in other countries, particularly developing nations. They are caused by the protozoan Entamoeba histolytica and are usually a sequela of colonic infection.

A careful search for malignant cells is essential whenever an aspirate shows abundant necrotic debris or acute inflammation, or both. Microbiologic culture helps to confirm a presumptive diagnosis of infection. For this reason, an on-site evaluation is crucial to ensure that aspirated material is sent for culture.

Echinococcal Cyst (Hydatid Cyst)

The larval form of Echinococcus granulosus, a dog tapeworm, causes infection in a variety of organs in humans, chiefly the liver. In one series of hepatic cysts 4 cm or larger in diameter, 10% were echinococcal cysts.⁵¹ The disease is endemic in the countries bordering the Mediterranean and Baltic seas, in South America, and in Australia and New Zealand. It is also seen in North America. Infection can be asymptomatic. Imaging studies reveal a solitary cyst, often with a fluid level. An outer, acellular, laminated membrane lines the cyst. The internal, germinal layer gives rise to daughter cysts, each of which contains scolices with numerous hooklets. Hooklets resist degeneration, but scolices can be lost in longstanding cysts with degeneration.

Although anaphylactic shock has been reported as an occasional complication of FNA,⁴⁷ its incidence has not been established, and successful aspiration without serious complications has been observed.^34,52–54 Other parasitic diseases that manifest with a liver mass include schistosomiasis, clonorchiasis, and visceral larva migrans.⁵⁵

Other Infections

Infection by the hepatotropic viruses (hepatitis A, B, and C viruses) is generally not evaluated by FNA, because the diagnostic changes of acute, subacute, and chronic hepatitis caused by these viruses are primarily architectural and not cytologic. Immunocompromised patients can develop hepatitis caused by cytomegalovirus (CMV) and herpesviruses, but such cases also result in diffuse liver disease and are rarely diagnosed by FNA.

Granulomas are seen in miliary tuberculosis, sarcoidosis, primary biliary cirrhosis, Hodgkin lymphoma, and drug reactions. Cytologic features are described elsewhere (see Figs. 2.15 and 2.4). The differential diagnosis of granulomatous inflammation includes a hepatic angiomyolipoma (AML) because the myoid cells of an AML have a syncytium-like appearance similar to that of epithelioid histiocytes. The presence of adipocytes and extramedullary hematopoiesis are clues to the diagnosis of AML.

Solitary Cysts

Solitary, nonparasitic cysts of the liver include the simple unilocular cyst, which is lined by cuboidal or columnar epithelium that resembles biliary epithelium. The aspirated fluid is typically hypocellular and nondiagnostic.

The ciliated foregut cyst is also solitary and unilocular and is lined by respiratory-type epithelium.

Bile duct cystadenomas and cystadenocarcinomas are multilocular tumors lined by mucinous epithelium and filled with watery or viscous fluid. The cystadenoma is lined by a single layer of benign mucin-producing cells, whereas the cystadenocarcinoma shows nuclear pleomorphism and stromal infiltration; the latter cannot be evaluated on cytologic preparations.

Cirrhosis

Cirrhosis, whether caused by alcoholic hepatitis, viral hepatitis, or other diseases, results in a disruption of normal liver architecture, with bands of fibrosis separating nodules of regenerating hepatocytes. Some regenerative nodules are larger than others and, on imaging studies, raise the specter of malignancy, primarily that of hepatocellular carcinoma (HCC), because patients with cirrhosis are at increased risk for developing HCC. Focal lesions in the setting of cirrhosis are often biopsied by FNA, although accuracy may be higher with needle biopsy or a combination of the two.²

The distinction between a cirrhotic nodule and a well-differentiated HCC can be problematic. When hepatocyte atypia is due to cirrhosis, there is a wide morphologic spectrum ranging from normal hepatocytes to markedly atypical ones, whereas an HCC is generally more monomorphic. Other features of HCC, rare or absent in cirrhosis, include an increased nuclear-to-cytoplasmic ratio, a thickened trabecular arrangement of hepatocytes surrounded by endothelial cells, acinar architecture, and atypical naked nuclei. Larger tissue fragments composed of normal hepatocytes are characteristic of cirrhosis, whereas trabeculae of variable thickness are seen in HCC.⁵⁶ The hepatocyte dysplasia of cirrhosis features loose hepatocyte clusters with minimal or no endothelial wrapping, cellular enlargement with preservation of a normal nuclear-to-cytoplasmic ratio, and cytoplasmic basophilia.⁵⁷ A combination of features permits the diagnosis in most cases of HCC.^{23,58, 59}

Specimens composed of hepatocytes without atypia are cytologically indistinguishable from the remainder of the conditions listed in the differential diagnosis; the diagnosis requires clinical-pathologic correlation. Nodular regenerative hyperplasia is a poorly understood condition in which small nodules of regenerating liver are scattered diffusely throughout the liver. Unlike cirrhosis, these nodules are not separated by bands of fibrosis, but patients often have portal hypertension and ascites.

Focal Nodular Hyperplasia

FNH is a benign liver lesion that possibly results from focal vasculopathy. It usually manifests as a solitary mass or, less commonly, several masses. Most patients are women in their third or fourth decade. The nodules usually contain a central scar, which can be appreciated on imaging studies. Histologic examination reveals nodules of hepatocytes that are separated by radiating fibrous septae that contain bile ductules.

These conditions are cytologically indistinguishable, and radiologic and clinical correlation is necessary. FNHs express the usual markers of hepatocellular differentiation, including HepPar1, thyroid transcription factor-1 (TTF-1) (cytoplasmic staining), arginase-1 (ARG-1), and CAM5.2, and canalicular staining for polyclonal carcinoembryonic antigen (CEA). A core biopsy can help by suggesting or confirming the diagnosis of FNH if bile ductules are present within the lesion: Bile ductules rule out an adenoma. Thus if FNH is suspected on the basis of imaging findings, and the rapid on-site assessment shows only normal hepatocytes and/or ductal cells, the cytologist can recommend a concurrent core biopsy.

The distinction between FNH and hepatic adenoma is a difficult but important one, inasmuch as hepatic adenomas, unlike FNH, have an increased risk of life-threatening hemorrhage and are linked to HCC. Molecular studies have confirmed the distinction between FNH and hepatic adenoma and have identified at least three different subtypes of hepatic adenoma.60,61 Data from molecular studies have led to the application of selected immunohistochemical markers (glutamine synthetase, liver fatty acid–binding protein, serum amyloid A or C-reactive protein, and β-catenin) in the distinction between FNH and hepatic adenoma in needle biopsies.⁶² For example, glutamine synthetase has a characteristic maplike staining pattern in FNH. They have not been widely applied to FNAs, however, and interpretation of these markers, especially in limited samples, can be problematic and is best deferred to specialists with experience in liver biopsies.

Hepatic Adenoma

Hepatic adenomas are rare benign neoplasms usually encountered in women under the age of 30, especially those with a history of long-term use of oral contraceptives. Patients often present with abdominal pain.⁶³ These lesions may rupture through the liver capsule, resulting in intraperitoneal hemorrhage, and they have been linked to HCC. Malignant transformation to HCC is rare but well documented.⁶¹ Histologically, they lack portal triads and are composed exclusively of hepatocytes. So-called naked arterioles—arterioles surrounded by scant connective tissue without bile ducts—are characteristic.

Hepatic adenomas express the usual markers of hepatocellular differentiation, including HepPar1, TTF-1 (cytoplasmic staining), ARG-1, and CAM5.2, and canalicular staining for polyclonal CEA. With regard to the distinction between FNH and hepatic adenoma, the presence of bile duct epithelium in the lesion helps to exclude hepatic adenoma,⁶⁴ but in practice clinical and radiologic correlation is necessary. Molecular studies have confirmed the distinction between FNH and hepatic adenoma and have identified several different subtypes of hepatic adenoma.^60,61 If needed, immunohistochemical markers (glutamine synthetase, liver fatty acid binding protein, serum amyloid A or C-reactive protein, and β-catenin) can aid in the distinction between FNH and hepatic adenoma in needle biopsy specimens,⁶² but interpretation is best deferred to specialists with experience in liver biopsies.

The cells of HCC have a higher nuclear-to-cytoplasmic ratio and more architectural derangement than is seen in adenomas.

Bile Duct Hamartoma and Adenoma

The bile duct hamartoma (von Meyenberg complex) is characterized by multiple small nodules dispersed throughout the liver and composed of haphazardly arranged bile ductules and fibrous stroma. The bile duct adenoma is usually a solitary subcapsular nodule less than 1 cm in diameter.

Hepatocellular Carcinoma

HCC accounts for 90% of all primary cancers of the liver. It is less common in the Unites States and Western Europe than in Africa and Asia. In the United States, a majority of cases are seen in the setting of cirrhosis. Most patients are over the age of 50, but children and younger adults can be affected. An alpha-fetoprotein (AFP) serum level greater than 4000 ng/mL is highly suggestive of HCC, but elevated titers are not present in all cases.

The tumor can manifest as a solitary nodule, as multiple nodules, or as diffuse liver enlargement. Histologically, HCCs are divided into classical and “special types.”⁶¹ The classical HCC has three architectural patterns that often occur in combination and can be appreciated cytologically, especially with cell block preparations: trabecular, pseudoglandular (acinar), and compact. In addition, classical HCC has myriad cytologic variants, including pleomorphic cells, clear cells, spindle cells, and fatty change. Bile is prominent in a minority of tumors, and a variety of cytoplasmic inclusions are occasionally encountered (Mallory hyaline bodies, globular hyaline bodies, pale bodies, and ground glass). The special types of HCC include fibrolamellar carcinoma, scirrhous HCC, undifferentiated carcinoma, lymphoepithelioma-like carcinoma, and sarcomatoid HCC.

There is a wide range of differentiation, from well-differentiated tumors that resemble normal liver, to poorly differentiated ones with marked nuclear pleomorphism and tumor giant cells (Fig. 13-9A and B). Because the cytomorphology and differential diagnosis are distinctly different at the two ends of the spectrum of HCC (i.e., well-to-moderately versus poorly differentiated), they are presented separately. HCCs express the usual markers of hepatocellular differentiation, including HepPar1, TTF-1 (cytoplasmic staining), ARG-1, and CAM5.2, and show canalicular staining for polyclonal CEA.

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