Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing (1). There has been a particular increase in the incidence of nonfunctional NETs, and most patients present with metastatic disease (1). The majority of NETs are indolent and asymptomatic at early stages, but medical intervention is necessary to control many symptoms derived from tumor volume and hormone secretion at advanced stages (2). NETs are generally heterogeneous, but in rare cases nonfunctional NETs change their phenotype into functional tumors (3, 4). We describe two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events.

In the present study, we described two rare cases of treatment-uncontrollable liver metastatic NETs. One was a nonfunctional small intestinal NET with liver metastasis and the other was a functional pancreatic NET (pNET; gastrinoma) with liver metastasis that underwent phenotypic transformation to a functional NET (gastrinoma) and an insulinoma, respectively, which eventually led to death. PNETs are divided into nonfunctional and functional NETs; nonfunctional NETs are far more common. Functional NETs are further subdivided based on the specific hormone secreted, including insulinomas, gastrinomas, glucagonomas, and VIPomas, among others. Although rare, the ability of pNETs to acquire new functional phenotypes has been previously reported (4). One study reported that non-functional NETs were transformed into insulinomas that cause repeated hypoglycemic episodes due to insulin hypersecretion (3). In our first case, non-functional small intestine, which is not a pNET, was transformed into a functional NET (gastrinoma). Owing to the rarity of this phenomenon, little is known about the mechanisms by which tumors transform into gastrinomas or insulinomas or gain function. The origin of NETs might be related to the type of hormone secreted, such as gastrin or insulin. In view of these cases, it is important that patients with end-stage nonfunctional NETs with expanding liver metastases be administered anti-acid medications such as proton pump inhibitors to prevent peptic ulcer after diagnosis of functional NETs such as gastrinoma.

Our second case was initially diagnosed as a functional pNET (gastrinoma) with treatment-uncontrolled liver metastasis, and it transformed into the addition of another functional NET (gastrinoma and insulinoma). Three previous case reports (five cases) have described the transformation of nonfunctional pNETs into functional pNETs (insulinoma) (3–5). However, this is the first report to describe a functional NET secreting gastrin and insulin. Therefore, advanced-stage NETs might be able to gain additional functions, allowing for the secretion of additional hormones.

Refractory hypoglycemia is an important cause of morbidity and mortality in patients with NETs and contributes to poor prognosis (3, 4). Due to the rarity of patients with functionally altered pNETs, data on the treatment of these patients are scarce. Therefore, treatment choices are limited to rare case reports or expert opinions. Systemic therapies (somatostatin analogs, tyrosine kinase inhibitors such as sunitinib, mTOR inhibitors such as everolimus, and PRRT) and liver-targeted therapies (e.g., transarterial chemoembolization) have been used in the treatment of nonfunctional pNETs with insulinoma transformation. However, none of these therapies have proven to be highly effective in these cases.

Lee et al. (6) previously presented a case of sunitinib-induced hypoglycemia occurring in a patient with nonfunctional pancreatic neuroendocrine carcinoma that had metastasized to the liver. In this case, endogenous hyperinsulinemia was observed, but insulin production by tumor cells was not evaluated because hypoglycemia improved with small doses of prednisolone. A recent report describes a similar rare case of transformation of a nonfunctional NET into an insulin-producing tumor, which, similar to the present case, metastasized to the liver (3). However, the hypoglycemia could not be attributed to sunitinib treatment, as various chemotherapy regimens were being used to treat the patient. In our case, severe hypoglycemia developed after treatment with sunitinib and thyroid hormones alone, but it has not been reported to induce hypoglycemia. These cases resemble nonfunctional pancreatic neuroendocrine carcinomas with liver metastases, suggesting that there may be a common mechanism, such as hepatic tissue environment. These reports also suggest the possibility of drug-induced transformation.

Interestingly, all previously published cases of NET transformation have been associated with hepatic metastasis, suggesting a drug-induced transformation or a role of the intrahepatic microenvironment in this process (3, 4). However, recent data in pituitary neuroendocrine cells suggest the presence of pluripotent progenitor cells that may be involved in the plasticity of the tumor phenotype (7). Both the cases, we experienced had high levels of liver function markers (i.e., aspartate transaminase and alanine aminotransferase) after transformation. However, it is unclear whether the elevated levels of liver function markers were caused by drug treatment or systemic deterioration. Although a subpopulation of clinically silent insulin-producing cells may become prominent in the liver, drug-induced transformation cannot be excluded from the clinical course.

The strengths of our report are the rarity of these cases and the importance of this phenomenon. By increasing the general awareness of this phenomenon, we believe that patients with NETs complicated by liver metastases can be managed appropriately. The limitations of this report are that (1) there are only two cases, (2) histological finding does not show the endocrine production (gastrin) before transformation in case 2, and (3) we lack histological assessment suggesting gastrin and insulin production in tumor cells at the time of transformation. Therefore, there is no direct evidence that the phenotype was caused by the tumor cells. Additionally, it is unclear whether the transformation was caused by environmental factors or whether it was drug-induced.

These cases and a review of the literature suggest that advanced-stage NETs with treatment-uncontrolled liver metastasis can transform from a nonfunctional NET into a functional NET or from one functional phenotype into the addition of another functional phenotype. Considering the possibility of such a serious life-threatening event, we recommend that oncologists and palliative medical doctors carefully monitor abdominal symptoms and hypoglycemic symptoms. Importantly, patients with nonfunctional NETs with end-stage disease and expanding liver metastasis need to take an anti-acid medication such as proton pump inhibitors to prevent peptic ulcers in the event of transformation into a functional NET, such as gastrinoma. More cases need to be accumulated to elucidate the mechanism of transformation, which is important for prevention.

In this case study, the patients were involved in the conduct of the study. The development of the research question was particularly based on the patients' experiences. The results of this study will be disseminated by the international report to patients and medical staff.

The studies involving human participants were reviewed and approved by Yokohama City University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

TKe and NK participated in study design. TKe, NK, MY, YKa, AO, NO, MI, TKo, TY, YKu, YH, MT, HI, TH, SF, AN, and YI participated in interpretation.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.