Fibrolamellar hepatocellular carcinoma (FL-HCC) is an uncommon variant of hepatocellular carcinoma (HCC). It typically occurs in younger patients without underlying liver disease. Grossly, FL-HCC is distinguished by the presence of fibrotic bands or a central stellate scar [1]. The FNA of biopsy of the fibrolamellar variant is often more discohesive than conventional HCC. The tumor cells are large with large nuclei and prominent nucleoli, oncocytic cytoplasm, cytoplasmic pale bodies, and lamellar fibrosis [1]. Pale bodies are well defined intracytoplasmic vacuoles with sharp outlines, corresponding to intracellular lumens lined by microvilli. Dense hyaline globules are also frequently present [1]. On cell blocks and biopsies, lamellar fibrosis appears as dense fibrous connective tissue arranged in parallel bands with spindle cell fibroblasts. Immunohistochemical stains may be helpful in differentiating FL-HCC from conventional HCC and other mimickers. The FL-HCC tumor cells usually express biliary and hepatocytic markers [2]. ; therefore, FL-HCC tumor cells may be positive for EpCAM (MOC-31) and cytokeratins 7, 8, 18 and 19; and they are positive for HepPar-1 and glypican-3. Immunostains for alpha-fetoprotein are negative [1]. The DNAJB1-PRKACA fusion transcript is found in 80-100% of FL-HCC [2,3]; this test is highly specific and may be used in the diagnosis of these lesions [3].

In many cases, regional lymph nodes are involved at the time of diagnosis. Distant metastases are most common in the lungs; however, pleural, pancreatic, lymph node and mediastinal metastases are also reported [4, 5, 6, 7]. Metastases or recurrence may appear several months to years after primary diagnosis and resection. Although 5-year survival rates as high as 70-85% have been reported for surgically resectable tumors, patients with disseminated nonresectable disease have a much worse prognosis, and the overall 5-year survival rate for FL-HCC is thought to be 30-34% [1]. As was the case in this patient, widely metastatic disease is often less responsive to chemotherapy.

Considering a potential liver primary, the differential diagnosis includes conventional HCC and cholangiocarcinoma. Conventional HCC usually affects older patients with history of cirrhosis and hepatitis B or C; the tumor cells show increased nuclear-to cytoplasmic ratios and thickened cell cords surrounded by endothelial cells. Conventional HCC tumor cells express glypican-3, arginase, and HepPar-1 and are negative for CK7 and EpCAM (MOC-31). Cholangiocarcinoma affects older patients with history of primary sclerosing cholangitis, hepatolitiasis, parasitic infestation by Clonorchis sinensis, and non-biliary cirrhosis. Cytologically, they appear as an adenocarcinoma with atypical cells with glandular differentiation, increased nuclear cytoplasmic ratios and anisocytosis; these cells are positive for CK7, CK17, CK19 and EpCAM (MOC-31) and are negative for HepPar1 and Glypican-3. Expression of CK20 and MOC-31 and negative staining for HepPar1 and Glypican-3 suggest a metastatic adenocarcinoma from other sites [1].

Given the FNA site in the neck, the differential diagnosis in this case also includes metastatic medullary thyroid carcinoma, paraganglioma (primary or metastatic), metastatic oncocytic neoplasms of the salivary gland, and metastatic germ cell tumors.

Medullary carcinoma of the thyroid could present at anytime from childhood to late adulthood, however it is most common in the fourth to sixth decades. Medullary carcinoma is reliably caused by mutations in the RET proto-oncogene; approximately 75% of cases are sporadic, and 25% of cases are hereditary. The hereditary cases are linked to the MEN syndromes as well as familial medullary carcinoma. The tumor cells secrete calcitonin, and serum calcitonin levels are often helpful in making the diagnosis. Cytologically, the tumor may show several patterns of organization, including single cells, syncitia, follicles, papillae, sheets, cords, or rosettes. The cells themselves may appear plasmacytoid, oncocytic, spindled, or large and bizarre with “endocrine atypia”. Although amyloid is frequently seen on histology, it may not be present in cytologic preparations. These tumors express TTF-1, CEA, synaptophysin, chromogranin and calcitonin and are negative for PAX-8 [8].

Paraganglioma may appear in either the anterior or posterior mediastinum, and may be associated with multiple endocrine neoplasia (MEN) II syndrome. The tumor cells are arranged in “zellballen” and have a variety of appearances. The cells may show lower grade features, such as round, eccentric nuclei with salt and pepper chromatin, resembling those of a carcinoid tumor. Alternatively, they may become large, polygonal and bizarre. The moderate to abundant cytoplasm may demonstrate metachromatic granules. Paraganglioma cells express neuroendocrine markers such as synaptophysin or chromogranin without keratin expression. Of note, the cell balls are often surrounded by sustentacular cells, which stain positively with S100 protein [9].

The oncocytic neoplasms of the salivary gland include oncocytoma, Warthin’s tumor, oncocytic carcinoma, or other lesions with oncocytoid features. These tumors show moderately large cells with abundant granular cytoplasm and round bland nuclei. The Warthin’s tumor would show these oncocytoid cells with a lymphocytic background, whereas the oncocytoma would not show an increase in lymphocytes; these latter tumors would not metastasize. Salivary gland cystadenocarcinoma and oncocytic carcinoma may metastasize to the neck. However, oncocytic carcinoma could present with a metastasis to the mediastinum. Oncocytic carcinoma generally shows cytologic atypia as well; the oncocytic carcinoma tumor cells are positive for CK7 and are negative for CK20, TTF-1, PAX-8, calponin, synaptophysin and chromogranin. Salivary duct carcinoma, oncocytic variant, is also included in the differential diagnosis; these lesions are cytologically similar to oncocytic carcinoma; in these cases, staining for androgen receptor and phosphotungstic acid haematoxylin (PTAH) may be helpful, androgen receptor is strongly positive in salivary duct carcinoma and oncocytic carcinoma is positive for PTAH.

Germ cell tumors of the mediastinum are much less common than their gonadal counterparts, however they can occur in younger patients, with a male predominance. All varieties of germ cell tumor may be found in the mediastinum, the most commonly found being the mature teratoma. Seminoma/germinoma of the mediastinum occurs almost exclusively in males and appears cytologically as a mixed population of small lymphoid cells and larger discohesive germ cells. The nuclei are large, hyperchromatic, have thick nuclear membranes, and prominent nucleoli. A characteristic feature of germinoma is the tigroid background. The tumor cells express PLAP, OCT3/4, and CD117. Embryonal carcinoma is composed of large cohesive clusters or papillary groups of poorly differentiated epithelioid cells. This tumor may be mistaken for a poorly differentiated adenocarcinoma; however, the tumor cells are positive for CD30, PLAP, OCT3/4, and CD57. Choriocarcinoma is rare in the mediastinum and has a very poor prognosis. Fine needle aspirates will show multinucleated syncytiotrophoblasts as well as mononuclear cytotrophoblasts. In appearance, the nuclei are overtly malignant with a distinct nucleoli. Yolk sac (endodermal sinus) tumors are more frequent in female patients, show papillary aggregates of large cells with malignant appearing nuclei, and are generally positive for cytokeratins. They may express fetoprotein, which may also be elevated in serum samples.