After reading the summary, try answering the three related multiple-choice questions below.
A 40-year-old woman presented with abdominal pain for 6 months. There was a history of ileal resection for a carcinoid tumor five years ago. CT scan showed a hypervascular liver mass without evidence of cirrhosis. Liver lobectomy showed a 6.0 cm tumor. Immunohistochemical staining showed that the tumor cells were HepPar 1(+), chromogranin(-) and focally synaptophysin(+).
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 27, and is a fibrolamellar carcinoma.
Criteria for Diagnosis and Comments:
The tumor shows a neoplastic proliferation of large polygonal cells with abundant eosinophilic granular cytoplasm. The cells are arranged in cords and solid nests. In some sections, the tumor cells show scattered lightly eosinophilic or clear cytoplasmic inclusions (“pale bodies”). Several bile plugs are identified. Fat is minimal to absent. Tumor cell nuclei are vesicular with a single large nucleolus, intranuclear cytoplasmic invaginations, and chromatin margination. The tumor cells are separated by plate-like stacks of collagen lamellae of varying thickness (lamellar fibrosis). The morphological features establish the diagnosis of fibrolamellar hepatocellular carcinoma (FLM).
FLM typically occurs in non-cirrhotic liver in young adults (mean age, 26 years) while only 6% of patients are 50 years of age at diagnosis. Many cases of FLM show elevated serum levels of des-carboxy prothrombin, neurotensin and vitamin B12 binding protein. The diagnostic utility of these three markers is limited, but these can be useful for monitoring tumor recurrence following surgery. A central scar is often present in FLM. The scar can also be present in lymph node metastases and can be visualized on imaging. FLM is not associated with any known risk factors.
A triad of morphological features should be adhered to strictly for the diagnosis of FLM: large polygonal tumor cells with abundant eosinophilic granular cytoplasm, prominent macronucleoli, and lamellar fibrosis. Lamellar fibrosis may not be observed in small biopsies of inadequately sampled tumors. Fat tends to be absent. Cytoplasmic granularity is due to the presence of numerous mitochondria, while “pale bodies” are composed of fibrinogen and/or albumin. PAS-positive and diastase resistant cytoplasmic globules are commonly seen and likely to represent glycoproteins. Some conventional HCC may have areas resembling FLM. It is likely that these tumors represent a variant of conventional HCC, as they tend to occur in older patients, are associated with high serum AFP and are often present in a background of viral hepatitis and/or cirrhosis. Acinar architecture and mucin can be seen in FLM, leading to confusion with cholangiocarcinoma or metastatic adenocarcinoma. Ultrastructural analysis shows abundant mitochondria, with some studies describing neurosecretory granules.
FLMs express markers of hepatocellular differentiation like Hep Par 1 and polyclonal CEA (canalicular pattern). AFP expression is absent in FLM, though rare cases may show focal expression in a few tumor cells. Glypican-3 is expressed in two-thirds of FLM compared to 80% of conventional HCC, while CK7 is expressed in nearly 80% of FLM compared to 20-30% of conventional HCC.
FLM lacks some of the molecular abnormalities often observed in conventional HCC like p53 mutations and beta-catenin mutations. In contrast to conventional HCC, portal or hepatic vein invasion is uncommon (<5% in FLM versus 40% in HCC). One-third of FLM patients present with regional or metastatic disease. Nodal and peritoneal metastases are more common than in conventional HCC. Lymph node involvement has been reported in up to 70% of cases and distant metastases occur in nearly 50% of cases. The preferred treatment is complete excision of the affected lobe with lymph node dissection. Relapse rate for FLM is high (36-100%) with a median time to relapse of 10-33 months. In the absence of resection, median survival is one year with zero 5-year survival
Many studies have reported that FLM has a better outcome than conventional HCC leading to the impression that FLM has a favorable natural history. Several well-designed studies have failed to confirm these observations. Irrespective of the prognosis of FLM compared to conventional HCC, it is important to note that FLM is an aggressive malignant tumor with a 5-year survival of 50-60%. FLMs occur in young patients, but almost 40% of patients die of the disease even when the tumor is localized to the liver at presentation. The outcome of FLM is likely to be similar to that of conventional HCC arising in non-cirrhotic liver. The better outcome in FLM compared to conventional HCC as a whole is likely to be related to absence of cirrhosis, which is a significant adverse factor in HCC. Chemotherapy and radiation have limited utility in FLM, although prolonged survival with multimodality therapy has been recently described. In some cases, unresectable tumors may become amenable to resection after platinum-based chemotherapy. When resection is not possible due to the location or extent of tumor, liver transplantation can be considered.
The triad of morphological features described above should be used to distinguish FLM from conventional HCC. The presence of central scar and pale bodies favors FLM, but the latter can be seen in conventional HCC as well, particularly the scirrhous variant. The fibrous stroma in the scirrhous variant can be mistaken for FLM, but the fibrosis usually does not have lamellar characteristics and the cytological features of FLM are absent. Some old reports describe “sclerosing HCC,” a variant of HCC with hypercalcemia and marked stromal fibrosis. It is best to avoid this term as majority of the tumors labeled sclerosing HCC in the past were likely intrahepatic cholangiocarcinomas. Radiation or chemotherapy can cause fibrotic changes in conventional HCC and may be confused with scirrhous pattern or, less commonly, FLM. It is important to distinguish FLM and conventional HCC as extended hepatic resection and lymph node dissection are more often performed in FLM. The correct diagnosis also enables recruitment of patients into appropriate treatment trials.
Both melanoma and FLM can have prominent nucleoli, but oncocytic features and lamellar fibrosis are not seen in melanoma. Immunohistochemical expression of S-100 and melanocytic markers like HMB-45, along with absence of Hep Par 1 and polyclonal CEA, distinguishes melanoma from FLM.
FLM may show focal neuroendocrine differentiation, raising the possibility of neuroendocrine neoplasms. In most cases, FLMs express less specific neuroendocrine markers like neuron-specific enolase, protein gene product 9.5, vasoactive intestinal peptide and calcitonin. Chromogranin and synaptophysin can be positive in FLM, but the expression is usually focal. Diffuse staining with chromogranin or synaptophysin strongly favors a neuroendocrine tumor, as these markers are generally negative or focally positive in most FLMs. Hepatocellular markers like Hep Par 1 and polyclonal CEA (canalicular pattern) are consistently negative in neuroendocrine tumors. In this case, immunohistochemistry was performed in view of the history of ileal carcinoid; however, it is not required for the diagnosis in most instances.
Due to the presence of central scar in focal nodular hyperplasia (FNH), it can be mistaken for FLM on imaging. FNH-like nodules can occur at the periphery of some FLMs, and it has been speculated that FNH is the benign precursor of FLM. However, this is unlikely and the FNH-like nodules at the periphery of FLM are probably due to local perfusion abnormalities. The ductular reaction and aberrant arterioles characteristic of FNH are not seen in FLM. The fibrosis in FNH does not have lamellar characteristics, and the typical cytological features of FLM are not present.