Overall, fibrolamellar carcinomas make up approximately 1 % of all hepatocellular carcinomas. Prior studies suggested a frequency of around 5 %, but more recent data from larger studies indicates a frequency closer to 1 % (Table 8.2). Fibrolamellar carcinomas have been reported from a wide variety of geographical locations, including most parts of the world. One study found no strong correlates between fibrolamellar carcinoma and white, black, Hispanic, or Asian ethnicities living in the USA [6]. However, many clinicians and scientists believe that fibrolamellar carcinomas are less common overall in Asian countries. There appears to be a small predilection in fibrolamellar carcinomas for males, but there is no evidence for a striking male dominance, as is seen in typical hepatocellular carcinoma.

One of the most distinctive and well-recognized features of fibrolamellar carcinoma is its occurrence in younger individuals. In fact, 50 % of cases occur between the ages of 17 and 30 and 80 % occur between the ages of 10–35 [7]. Nonetheless, an important diagnostic point is that fibrolamellar carcinomas are not the most frequent form of liver cancer in children and young adults. Instead, typical hepatocellular carcinomas are still the most common and account for 60–80 % of cases [1, 8–10]. Thus, young age is not a finding on which a diagnosis of fibrolamellar carcinoma can be based.

Fibrolamellar carcinoma most often presents with vague, nonspecific abdominal pain, weight loss, and malaise. However, there is a wide variety of less common findings at presentation. Of these, one recurrent theme is biliary obstruction secondary to direct tumor growth into the biliary tree or to compression by metastatic deposits in hilar lymph nodes. Gynecomastia in males is also a rare but distinctive finding at presentation.

Serum alpha-fetoprotein (AFP) levels are normal in essentially all cases and an elevated serum AFP level makes the diagnosis of fibrolamellar carcinoma unlikely. There are some reports of fibrolamellar carcinomas with significantly elevated serum AFP levels, and it is possible that this might occur in rare cases, but overall it seems likely that most of these cases are misdiagnosed.

A number of serum proteins are elevated in individuals who have fibrolamellar carcinoma, but none are sufficiently sensitive or specific to be widely used clinically. These proteins include transcobalamin I, transcobalamin 2, fibrinogen, and neurotensin. In addition, PIVKA-II (protein induced by vitamin K absence/antagonist-II) is commonly elevated in both typical hepatocellular carcinomas and in fibrolamellar carcinoma. While these serum findings are not useful for diagnosis, they can be useful in individual cases to monitor for response to tumor therapy and to monitor for tumor recurrence.

Prognostic factors are shown in Table 8.3. After resection of primary disease, approximately 55 % of cases will recur within the first 5 years [11]. Recurrent disease is intrahepatic in about 40 % of cases, involves extra-abdominal organs such as the lungs in about 40 % of cases, and presents with peritoneal and/or lymph node disease in about 20 % of cases [11].

Lymph node metastases are identified at presentation in approximately two thirds of fibrolamellar carcinoma cases [12–15]. In fact, lymph node metastases at the time of presentation are more common in fibrolamellar carcinoma than in typical hepatocellular carcinoma [3]. The involved lymph nodes are commonly regional nodes [16–18], including celiac [16, 18], gastric [19], and para-aortic lymph nodes [16, 19].

Direct extension outside of the liver is also common at presentation. In one study, 42 % of fibrolamellar carcinomas extended into the adjacent fat planes by imaging studies [13]. Direct extension into adjacent organs can also be seen, including the stomach [19], diaphragm [13], and pancreas [13, 20]. A subset of cases can also demonstrate widespread peritoneal disease at presentation [13–16, 21–23]. Other cases tend to spread by isolated or a small number of metastases, a pattern that can often be treated with surgery.

Overall, fibrolamellar carcinomas tend to be more common in the left lobe of the liver, but frequently involve both lobes. In 80–90 % of cases a single large tumor is present. In cases with multiple tumor masses, there tends to be one dominant mass. Fibrolamellar carcinomas tend to be large at the time of resection, commonly measuring 10 cm or more in greatest dimension. Fibrolamellar carcinomas range in color from yellow to pale tan (Fig. 8.1) and range in consistency from soft to firm. The tumors can feel gritty when microcalcifications are prominent. In cases with prominent pseudoglands, the tumor can have areas that are grossly tacky and mucinous. A central scar is found in about two thirds of cases. Occasionally, the tumors may contain small foci of necrosis or areas of intratumoral hemorrhage. Gross vascular invasion is seen in up to 25 % of cases [16]. The background liver is non-cirrhotic, but a rim of inflamed and fibrotic tissue is often present at the interface of the fibrolamellar carcinoma with the non-tumor parenchyma. Sections from this area are helpful and important for looking for angiolymphatic invasion, but are not useful for examining the background liver for underlying liver disease.

Tumor cells are large and polygonal, with abundant eosinophilic cytoplasm that is rich in mitochondria and lysosomes (Fig. 8.2). The nuclei often have vesiculated chromatin and large nucleoli (Fig. 8.3). These distinctive cytological findings, when combined with the intratumoral fibrosis, are the defining H&E features of fibrolamellar carcinoma.

There are a variety of other histological findings that are common in fibrolamellar carcinoma, but they are neither necessary nor specific for the diagnosis. The most distinctive are pale bodies. Pale bodies are round amphophilic inclusions found in approximately 50 % of cases (Fig. 8.4). Pale bodies do not show any clear spatial relationships with fibrosis, the center or periphery of the tumor, or tumor vasculature. They are immunoreactive for a number of different proteins, including vimentin, but the principal protein component is not known. Their cause is also not known, but presumably reflects a defect in protein folding or protein secretion. Hyaline bodies can also be found in 20–30 % of cases, but can be more subtle histologically than pale bodies, and their true frequency is not clear. Hyaline bodies are eosinophilic cytoplasmic inclusions of unclear etiology and composition (Fig. 8.5). Similar to pale bodies, there does not appear to be any strong spatial correlates and hyaline bodies appear to be somewhat randomly found in tumors. Pale bodies and hyaline bodies can be found in the same tumor, but are generally not found in the same areas within a tumor.

Approximately 10 % of fibrolamellar carcinomas can have gland-like structures, or pseudoglands (Fig. 8.6). The pseudoglands are ovoid cystic structures lined by tumor cells, have a wide range of sizes, and in some cases appear to arise from dilated canalicular like structures. The secretions within the pseudoglands are mucicarmine positive in about half the cases and are Alcian blue positive in most cases. Because of the mucicarmine positivity, some have suggested these are true glands and not pseudoglands, leading to diagnoses of combined fibrolamellar carcinoma and cholangiocarcinoma. Despite the mucicarmine staining, the data at this point suggests they should be classified as ordinary fibrolamellar carcinomas and not as combined tumors.

Metastases to lymph nodes and other organs typically look like the primary tumor, but in some cases metastatic disease can have a prominent pseudoglands component (Fig. 8.7). Since these pseudoglands can produce mucin, they can be mistaken for a cholangiocarcinoma. However, a history of fibrolamellar carcinoma is often present and will aid in the proper diagnosis. In other cases, immunostains can be used to differentiate fibrolamellar carcinoma from adenocarcinoma, as fibrolamellar carcinomas will be positive for HepPar1, arginase, CK7, and CD68.

Other common tumor findings include microcalcifications. The calcifications can be dystrophic, featuring irregular deposits in areas of remote necrosis, fibrosis, or the walls of larger vessels. In other cases, the microcalcifications appear to represent calcification of single tumor cells (Fig. 8.8). Mild macrovesicular steatosis can occasionally be seen, even in cases without fat in the background liver (Fig. 8.9). Sometimes small pseudoglands can be similar in size to fat droplets and the two can appear similar at low power, but higher power examination readily separates the two findings. Tumor cholestasis is also common, with bile located within the cytoplasm of tumor cells or within canalicular like structures between tumor cells (Fig. 8.10). This frequent cholestasis is commonly associated with copper accumulation within tumor cells. However, copper accumulation is also found in ordinary hepatocellular carcinomas that are cholestatic and thus is not a specific finding. Finally, occasional benign isolated bile ducts can be found entrapped within the growing front of the tumor (Fig. 8.11).

Vascular invasion is present in 40–50 % of fibrolamellar carcinomas on histological analysis [8, 14, 16]. Vascular spread into the portal veins of nearby portal tracts is a common pattern of angiolymphatic invasion. The best place to identify vascular invasion is sections taken at the tumor–nontumor interface.

Perineural invasion can be seen when tumors involve the hilum of the liver (Fig. 8.12). In addition, tumor spread into the soft tissue of the liver hilum is a common finding and one that does not readily fit into current tumor staging systems. Nonetheless, both perineural invasion and invasion of the liver hilum soft tissue can be included in pathology reports and presumably indicate a worse prognosis.

Fibrolamellar carcinomas show unequivocal hepatocellular differentiation by immunohistochemistry, but also show expression of proteins more commonly associated with biliary differentiation. The frequency of staining with commonly used diagnostic immunostains is shown in Table 8.4. Neuroendocrine features have been noted in some fibrolamellar carcinomas by several authors [24–26]. Most fibrolamellar carcinomas are negative for chromogranin and synaptophysin by immunohistochemistry [27, 28], but occasional cases are chromogranin positive [17].