A 60-year-old woman with history of intrahepatic cholangiocarcinoma presented with severe thoracic pain secondary to a large left-sided thoracic mass with extension to the thoracic spine and the pleural cavity. The patient underwent a resection of the tumor.
The correct answer is ...
Metastatic intrahepatic cholangiocarcinoma, cholangioblastic variant.
Cholangiocarcinomas (CCA) are classified into intrahepatic, perihilar, and extrahepatic CCA. Intrahepatic cholangiocarcinomas are now generally subdivided into two broad categories: the large duct and small duct types. The large duct subset is usually perihilar and characterized by infiltrative glands in a desmoplastic stroma; these subtype of CCA frequently harbor mutations in KRAS and TP53. The small duct subset is typically peripherally located within the liver parenchyma characterized by glands lined by cuboidal cells embedded in an hypocellular sclerotic stroma. This subtype is frequently associated with mutations in IDH1 or IDH2, or with gene fusions involving the FGRF2.
A new NIPBL-NACC1 gene fusion has been identified in a subset of intrahepatic cholangiocarcinomas. This histologic entity has been called cholangioblastic variant of intrahepatic cholangiocarcinoma. (CbvICCA).
Histologically, these tumors present a variety of architectural patterns, including nested/organoid and trabecular architecture. Of note, neoplastic cells may be arranged in acinar structures with pink luminal secretions resembling thyroid gland follicles, so called ‘follicular-like’ type architecture. This architectural pattern is considered distinctive and should raise this diagnostic possibility in the right clinical context. Cytologically, neoplastic cells are usually large, characterized by abundant eosinophilic cytoplasm and large nuclei with vesicular chromatin, and occasional prominent nucleoli.
CbvICCA are characterized by a diffuse strong immunoreactivity for inhibin A and show patchy expression of neuroendocrine markers, such as synaptophysin and chromogranin, but no labeling for INSM1.
The new discovered fusion gene associated with this entity, NIPBL-NACC1, connects exon 8 of NIBPL to exon 2 of NACC1. NIPBL-NACC1 gene fusion may result in dysregulated expression of a substantially intact NACC1 protein, neoplastic development, as observed in other malignancies. Small series studies suggest that these tumors tend to occur more frequently in young patients and is associated with a more aggressive behavior. Additional studies are needed to further understand this fusion, its biology, and association with prognosis.
The differential diagnosis of this entity is broad, and immunohistochemical techniques significantly assist in narrowing the differential diagnosis, mostly in ruling out other sites of origin.
The main clinicopathologic differential diagnosis for these neoplasms is that of well-differentiated neuroendocrine neoplasms metastatic to the liver. Of note, before the gene fusion NIPBL-NACC1 was described, many of these tumors were previously classified as well-differentiated neuroendocrine neoplasms given the morphology and immunohistochemical profile. Although cholangiocarcinoma can be patchy positive for synaptophysin and chromogranin, the characteristic morphology along with INSM1 negativity should raise this diagnostic possibility.
Typically, a well-differentiated neuroendocrine neoplasm with abundant eosinophilic cytoplasm would demonstrate diffuse labeling for neuroendocrine markers including synaptophysin and INSM1.
On the other hand, other primaries that also have patchy neuroendocrine marker expression, such as metastatic breast carcinoma with neuroendocrine differentiation and metastatic acinar cell carcinoma of the pancreas, should also be considered.
Maria Olave Martinez, M.D.
Fellow, Surgical Pathology
Rondell Graham, M.B.B.S.
Consultant, Anatomic Pathology
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science