Insulinoma of the pancreas with insular–ductular differentiation in its liver metastasis – indication of a common stem-cell origin of the exocrine and endocrine components

Abstract

We describe an insulinoma of the pancreas in a 56-year-old patient, which showed insular-ductular differentiation in its liver metastasis. Although the primary tumor was uniformly endocrine in nature with insulin production, the metastasis contained two distinct cell types in organoid arrangement. One cell type was insulin-positive and was arranged in islet-like structures; the other was insulin-negative but distinctly pan-cytokeratin and cytokeratin 7 positive and arranged in ducts. In the primary tumor and the metastasis, the tumor cells were surrounded by a desmoplastic stroma. As to the histogenesis of the tumor and its metastasis, we discuss the following possibilities: (1) the tumor cells might derive from a common stem cell that matures into two phenotypically different cell lines, resembling the situation in embryogenesis and (2) one tumor cell type originates from the other by transdifferentiation (metaplasia). We conclude that the parallel occurrence of endocrine and ductal differentiation supports the concept that, under certain conditions, islet cells and ductular cells may also originate from islets and that mixed endocrine/exocrine pancreatic tumors do not necessarily arise from totipotent duct cells but might also have a primary endocrine cell origin.

Mixed ductal‐endocrine carcinoma derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreas identified by human telomerase reverse transcriptase (hTERT) expression

“…In PDACs, scattered endocrine cells seem to be non-neoplastic; in several cancers, endocrine cells have no proliferative activity and are usually absent from metastases [8,9]. Some human pancreatic cancers have also been reported to develop ductal carcinoma differentiation within metastasis from a pancreatic endocrine neoplasm [22]. In other pancreatic tumors, such as acinar cell carcinoma and pancreatoblastoma, scattered endocrine cells most likely represent an integral component of the tumor [8,24].…”

“…Journal of Surgical Oncology However, truly mixed tumors have to be distinguished from exocrine neoplasms with scattered endocrine cells [21] or transformation of endocrine cells into duct cells [8,22]. Particularly, non-neoplastic ductules within endocrine tumors, or cells with endocrine features, have been observed in the pancreatic tissue of patients with chronic pancreatitis and PDACs [10,23].…”

Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas

“…Even though it is now believed that pNETs arise from multipotent pancreatic stem cells 10,11 , there is still discussion as to whether they originate from the islets of Langerhans 10 -12 . The World Health Organization (WHO) first introduced a system for naming and classifying endocrine tumours of the pancreas in 2000.…”

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas

“…Several groups have reported the activation of different embryonic cell signaling pathways (ie, Notch and Hedgehog) in gastroenteropancreatic NETs, which can be perceived as indirect evidence for the existence of pNET CSCs [12]. Furthermore, the occurrence of cells with insular-ductular differentiation in an INS liver metastasis of a patient with a purely endocrine primary INS has been implicated to support the concept that the endocrine and exocrine components have a common stem-cell origin [13]. Moreover, in a previous study we have demonstrated that canine INS contain a small population of amphicrine cells with a stem cell phenotype, expressing both endocrine hormones as well as exocrine enzymes [14].…”