Liver FNA is most often performed transabdominally under ultrasound or computed tomography (CT) guidance, typically by a radiologist. The advantages of ultrasound over CT guidance include real-time needle guidance, speed of procedure, excellent discrimination between solid and cystic lesions, lower cost of equipment, portability, and lack of radiation exposure. CT guidance offers better visualization of some lesions, particularly small ones.

MRI-guided procedures are possible, but require special equipment and are thus very expensive, and they rarely have any advantage in liver FNA. Transjugular biopsies performed using interventional radiology are rarely indicated (except for patients with impaired clotting, morbid obesity, or gross ascites) but may be attempted. “Blind” percutaneous liver biopsies (without image guidance) may be used in evaluation of diffuse liver abnormalities, but they are not typically used for targeting space-occupying lesions.

The newest technique is endoscopic ultrasound-guided FNA (EUS-FNA), which has a sensitivity of 82–94 % and specificity 90–100 % for space-occupying lesions. In these procedures, the liver is accessed via the stomach or small intestine. The left lobe of the liver is easily accessed, and the liver hilum, proximal right lobe, gallbladder, and perihilar lymph nodes can potentially be accessed. The technique is good for detecting and assessing a number of lesions for staging, and the diagnostic yield is higher for metastatic lesions than for primary HCC.

The approach to image-guided FNA is discussed in further detail in Chap. 1.

The sensitivity of liver FNA ranges from 67 to 100 % and the specificity from 87 to 100 %. The overall accuracy is 80–95 %. The sensitivity and specificity for liver malignancy are 90 % and 100 %, and positive predictive value for malignancy approaches 100 %. Combined FNA and NCB has a higher sensitivity (85–100 %) compared to either FNA (62–100 %) or NCB alone (69–91 %).

The risk of complications is low, but the most commonly encountered ones include pain, hemorrhage, and infection. To control the associated pain, local anesthetic is typically provided with lidocaine, but the liver parenchyma cannot be anesthetized. Hemorrhage occurs in less than 1 % of patients. Intra-abdominal bleeding is the most severe potential complication, however transfusion is rarely required. The procedure is typically performed using sterile technique, and the rate of infection is less than 1 %. Prophylactic antimicrobials are not routinely given. The risk of tumor seeding due to the procedure is generally regarded as <0.01 %, though small series have reported a higher incidence of seeding in HCC (0.003–5.0 %). The risk of mortality is approximately 1 in 10,000–12,000.

Though generally a low-risk procedure, there are certain patients in whom liver FNA is contraindicated. Patients with severe bleeding disorders that cannot be corrected with therapy and those unable to remain still during the procedure or cooperate with positioning may be ineligible. Morbid obesity or massive ascites may impair the ability to perform transabdominal percutaneous liver biopsy, so the transjugular approach may be indicated. Some authorities suggest that aspiration of hepatocellular carcinoma carries a higher risk of bleeding and/or seeding, thus the procedure risks should be evaluated carefully in a borderline patient who is suspected to have HCC.

Complications of and contraindications to FNA are discussed in further detail in Chap. 1.

Although normally present in infants, extramedullary hematopoiesis (EMH) is an abnormal finding in adults and older children. It is seen in adults as a result of bone marrow failure. Aspirates are composed of all of the elements normally present in a bone marrow aspirate including erythroid, myeloid, and lymphoid cells at various stages of maturation (Figs. 3.10 and 3.11). The presence of megakaryocytes is the most striking feature and may be mistaken for neoplasm such as a high grade sarcoma or carcinoma if EMH is not considered (Fig. 3.12). The presence of a mixed hematopoietic population in the background should raise the possibility of EMH.

Hepatic hemangiomas are very common lesions, found in up to 20 % of the general population. They have a female predominance and typically range from 1 to 10 cm in size. Small lesions are usually asymptomatic, but large ones may be symptomatic causing abdominal pain, anorexia, or nausea. There is a low risk of rupture, but these lesions may enlarge during pregnancy or during oral contraceptive use. They are most often solitary and have a characteristic radiographic appearance, thus they are not usually aspirated. If aspirated, cytopathologic features include abundant blood, scant paucicellular fibrous tissue, and, rarely, small groups of endothelial cells having spindle-shaped nuclei with tapered ends forming a swirling or streaming pattern (Figs. 3.13 and 3.14). CB or NCB can be quite useful if even a small amount of the lesion is obtained. The diagnosis should be considered in samples deemed “inadequate.”

Key features:

Differential diagnosis:

The differential diagnosis includes unsampled neoplasm as the lesion may appear insufficient for diagnosis. If spindle cells are encountered, one should consider spindle cell neoplasms such as angiosarcoma, epithelioid hemangioendothelioma, metastatic gastrointestinal stromal tumor (GIST), or leiomyosarcoma. The degree of pleomorphism is typically much greater in the spindle cell neoplasms, and CB or NCB may be quite useful in distinguishing these lesions.

Over half of cases of cirrhosis in the United States are caused by alcoholic liver disease. Other common causes of cirrhosis include viral hepatitis, hemochromatosis, nonalcoholic steatohepatitis, and autoimmune diseases. FNA is not useful to grade cirrhosis, but cirrhotic liver may be sampled as part of a workup for a solid mass, thus knowledge of the cytopathologic features is essential. Cirrhosis is characterized histologically by diffuse fibrous bands separating nodules of hepatocytes that show varying degrees of atypia including increased nuclear size and prominent nucleoli (Fig. 3.15). Masson trichrome stain highlights the fibrosis (Fig. 3.16). Similarly, morphologic features range from normal appearing to variably atypical hepatocytes. Focal marked anisocytosis may be present, and binucleation is not uncommon. The nuclear to cytoplasmic ratio may be normal to slightly increased. Prominent nucleoli and intranuclear inclusions are commonly seen. Typically there is some fibrous tissue aspirated and admixed with hepatocytes, and there is usually abundant bile duct epithelium present, in contrast to hepatic adenomas and hepatocellular carcinoma (Figs. 3.17, 3.18, and 3.19).

Key features:

This typically asymptomatic condition is often discovered incidentally in patients undergoing imaging for an unrelated complaint. It is more common in women, particularly in the age range of 20–40 years. Formation of FNH is not associated with oral contraceptive use, however use may result in enlargement and increase in vascularity. There is no association with hemoperitoneum. They are usually less than 3 cm in size and arise in noncirrhotic livers. This condition is either treated with local or segmental liver resection or followed radiographically (small lesions). Radiographically, a characteristic central stellate scar is usually evident, and tissue diagnosis is often not necessary. Histologically these lesion resemble “focal cirrhosis,” that is nodules of bland hepatocytes surrounded by bands of fibrosis with bile duct proliferation at the periphery of the nodule. No portal tracts or central veins are present within the lesion. Cytopathologically, normal to hyperplastic hepatocytes may show binucleation and may be present as two cell thick groups. Otherwise the hepatocytes show normal morphology and nuclear to cytoplasmic ratio. Fatty change may be seen, and numerous bile ducts are present, some forming long tubules. Fibrous tissue is typically sparse on aspirate smears. In contrast to HCC, there is no endothelial proliferation and the reticulin framework is intact (Figs. 3.20 and 3.21).

Differential diagnosis:

Correlation with radiographic findings to rule out cirrhosis or normal liver is essential to the diagnosis. Based on morphology alone, the differential includes well-differentiated HCC, which typically occurs in a cirrhotic liver and shows increased thickness of cell plates (>2 cells), which can be confirmed with reticulin. A hepatic adenoma is also in the differential, but the two cannot be reliably distinguished based on cytology alone.

Hepatic adenomas (HAs) are much more common in women than men and are seen most often in patients under 30 years of age. They are strongly associated with oral contraceptive use (>5 years). They are often symptomatic, and abdominal pain is common, particularly with intratumoral hemorrhage. Spontaneous rupture and hemoperitoneum occur in 10 % of cases, especially during menstruation, pregnancy, or postpartum. Radiologically, they are seen to arise in noncirrhotic livers and are most often solitary. They are homogeneous lesions with no central scar, and hemorrhage within the lesion suggests adenoma. On histologic sections, HAs are well-defined neoplasms consisting of hepatocytes with normal (nonthickened) hepatic plates (one to two cells thick). They lack portal triads and central veins, and steatosis is common. FNAs are hypercellular and show a monotonous population of normal hepatocytes. Hepatocytes occur singly and in cords two cells thick and show minimal nuclear atypia with normal nuclear to cytoplasmic ratio. Bile ducts should be absent, though the diagnosis of HA is not completely excluded by the presence of bile ducts, as they may be sampled from surrounding normal liver.

Differential diagnosis:

Just as in FNH, it is essential that one correlate the cytomorphology with radiographic findings to rule out cirrhosis or normal liver. The differential includes a well-differentiated HCC and immunostains, including CD34, can be helpful in making the distinction. FNH is also in the differential, but the two cannot be distinguished reliably on FNA.

These are small (<2 cm) lesions, commonly encountered during intra-abdominal surgery due to their subcapsular location. They are well circumscribed and histologically composed of a bland bile duct proliferation and fibrosis. They are not often aspirated, but when they are, they show abundant bile duct epithelium in flat sheet and scant hepatocytes.

Differential diagnosis:

The differential diagnosis includes von Meyenburg complex, which typically show multiple lesions and have intraluminal bile present. Well-differentiated cholangiocarcinoma or metastatic adenocarcinoma may be considered, though bile duct adenoma should not have nuclear atypia. Radiographic and clinical correlation is also important.

Angiomyolipoma (AML) is a rare primary liver tumor. It occurs in male and female patients with similar incidence, and is most common in patients 30–40 years of age. Most are asymptomatic. They display similar histologic and cytomorphologic findings to AML in kidney, including a combination of fat, smooth muscle and blood vessels. The fat component is more often scant or absent in liver versus kidney. Spindle cell lesions are considered in the differential. The main pitfall is the epithelioid variant, which may be misinterpreted as carcinoma, particularly HCC, due to cells with abundant eosinophilic cytoplasm and formation of trabeculae. The distinction is based on absence of cirrhosis in background liver and lack of nucleoli, bile, and fatty change within tumor cells. Immunoreactivity for HMB-45 and SMA, along with negativity for cytokeratin, confirms the diagnosis of AML.

This rare lesion is seen predominantly in middle-aged women and is associated with cystadenomas of the pancreas and ovary. Patients may present with abdominal pain. They have a thick septated wall and histologically are lined by a single layer of mucinous epithelial cells (flat, cuboidal, or columnar). The stroma in women shows ovarian morphology and is positive for ER and PR. Importantly, up to 25 % undergo malignant transformation to cystadenocarcinoma, so surgical resection is indicated. On cytology smears, they are composed of benign-appearing ductal epithelium with mucinous cells and goblet cells having bland, uniformly sized nuclei without nucleoli. There is often extracellular mucin. Ovarian stroma is not typically aspirated, and there should be absent or very few hepatocytes (from needle pickup only). Hepatobiliary cystadenocarcinoma is the main differential diagnostic consideration and shows atypical glandular epithelium. Surgical resection may be required to distinguish the two.

Improvements in dynamic imaging techniques, such as contrast-enhanced ultrasound and dynamic magnetic resonance imaging (MR), have greatly increased the accuracy of diagnosis of hepatocellular carcinoma in patients with cirrhosis, obviating the need for tissue confirmation in many cases with the classic presentation of HCC. Thus, the nodules that cytopathologists are asked to evaluate are smaller (less than 2 cm) and show fewer of the characteristic clinical and radiographic features of HCC than hepatic nodules evaluated in the past.

Cholangiocarcinoma is the second most common primary liver malignancy, though far less common than HCC. It should be distinguished from metastatic carcinomas, which are discussed in detail later in this chapter.