Abstract
Insulinomas are rare functional pancreatic neuroendocrine tumors. While most insulinomas are indolent and cured after surgery, 10–15% of cases show aggressive or malignant tumor behavior and metastasize locally or to distant organs. Patients with metastatic insulinoma survive significantly shorter. Recognizing aggressive insulinomas can help to predict prognosis, guide therapy and determine follow-up intensity after surgery. This review offers a summary of the literature on the significant clinical, pathological, genetic and epigenetic differences between indolent and aggressive insulinomas. Aggressive insulinomas are characterized by rapid onset of symptoms, larger size, expression of ARX and alpha-1-antitrypsin and decreased or absent immunohistochemical expression of insulin, PDX1 and GLP-1R. Moreover, aggressive insulinomas often harbor ATRX or DAXX mutations, the alternative lengthening of telomeres phenotype and chromosomal instability. Tumor grade and MEN1 and YY1 mutations are less useful for predicting behavior. Aggressive insulinomas have similarities to normal alpha-cells and non-functional pancreatic neuroendocrine tumors, while indolent insulinomas remain closely related to normal beta-cells. In conclusion, indolent and aggressive insulinoma are different entities, and distinguishing these will have future clinical value in determining prognosis and treatment.
Introduction
Insulinomas are neuroendocrine tumors that autonomously secrete insulin and usually arise within the pancreas. Insulinomas are uncommon tumors, with an incidence of 1–4 per million per year and are usually considered ‘benign’ or ‘indolent’ (Service et al. 1991, Svensson et al. 2022). Patients are typically cured after surgical resection without the need for extensive additional lymph node resections. Nevertheless, 10–15% of insulinomas display ‘malignant’ tumor behavior and may metastasize locally or to distant organs. As the definitions for malignancy are ambiguous, non-metastatic insulinomas will be referred to as ‘indolent’ and metastatic insulinomas as ‘aggressive’ from here on, reflecting their biological behavior and in line with the upcoming WHO classification of endocrine and neuroendocrine tumors (La Rosa et al. 2023). For clarity, the use of the term indolent does not refer to the clinical presentation of hypoglycemia, which may be severe in non-metastatic disease. Patients with aggressive insulinoma have lower survival compared to patients with indolent insulinoma: 5-year-survival has been reported to be 94.5–100% for indolent and 24–66.8% for aggressive disease (Yu et al. 2017, Camara-de-Souza et al. 2018, Veltroni et al. 2020, Kurakawa et al. 2021, Sada et al. 2021, Svensson et al. 2022).
In patients who present with localized insulinoma, a reliable strategy to predict metastatic behavior is currently not available and an unmet clinical need, as additional surgical resections or more intense follow-up may be warranted.
Recent insights into the genetic and epigenetic landscape of insulinoma have significantly increased our understanding of the pathogenesis and (endocrine) differentiation of these tumors. Insulinomas can appear in the setting of familial syndromes (e.g. the multiple endocrine neoplasia type 1 (MEN1)-syndrome) or sporadically. In this review, we will provide a concise overview of the clinical, pathological, genetic and epigenetic characteristics of sporadic insulinomas, providing means to distinguish aggressive from indolent disease.
Clinical insights
The classic clinical presentation of insulinoma is endogenous symptomatic hypoglycemia. In order to confirm the diagnosis of symptomatic hypoglycemia due to endogenous hyperinsulinemia, insulin and usually c-peptide and proinsulin concentrations have to be demonstrated to be inappropriately elevated during an episode of hypoglycemia (de Herder et al. 2000).
Indolent vs aggressive insulinomas
Several studies have addressed the clinical presentation of indolent vs aggressive insulinoma. Patients with aggressive insulinomas have been shown to present after a shorter duration of symptoms and display more extensive hypoglycemia and higher insulin levels and have more rapid onset of hypoglycemia after fasting (Yu et al. 2017, Camara-de-Souza et al. 2018, Veltroni et al. 2020, Sada et al. 2021). Primary pancreatic tumors are larger in patients with aggressive insulinomas.
In order to localize an insulinoma, CT, MRI and endoscopic ultrasound are first-line imaging modalities (Rosch et al. 1992). In addition, somatostatin receptor (SSTR), dihydroxyphenylalanine and glucagon-like peptide-1 receptor (GLP-1R) imaging can be used, if available (Refardt et al. 2022). GLP-1R imaging is more sensitive than SSTR imaging but is of limited use for aggressive cases, as only a small proportion of aggressive insulinomas express GLP-1R (Wild et al. 2011, Sowa-Staszczak et al. 2013, Cases et al. 2014, Waser et al. 2015). As SSTR2 is regularly expressed in both indolent and aggressive insulinoma, SSTR imaging is more effective for visualizing aggressive cases (Wild et al. 2011, Prasad et al. 2016, Nockel et al. 2017).
Hypoglycemia can be treated with dietary interventions and diazoxide. In addition, somatostatin analogs, glucocorticoids and – in advanced disease – everolimus are used (Kulke et al. 2009). Solitary pancreatic insulinomas are usually treated by surgery with curative intention. In selected cases, endoscopic radiofrequency ablation or ethanol ablation results in symptom control with few side effects (Hofland et al. 2019, El Sayed et al. 2021). In case of metastatic insulinoma, the treatment options are in line with the guidelines for metastasized PanNETs, with a preference for debulking strategies such as metastasectomy, radiofrequency ablation, electroporation or embolization. Systemic anti-tumor therapies for aggressive insulinoma include long-acting somatostatin analogs, peptide receptor radiotherapy, everolimus, sunitinib and chemotherapy (Zandee et al. 2019).
Pathological insights
Indolent vs aggressive insulinomas
The most consistent indicator of insulinoma behavior is pathological tumor size (Raffel et al. 2010, Alkatout et al. 2015, Yu et al. 2017, Camara-de-Souza et al. 2018, Henfling et al. 2018, Andreassen et al. 2019, Hackeng et al. 2020, Sada et al. 2021). Although cut-off values (if used) differ per study, virtually all indolent tumors are smaller than 3 cm, while aggressive tumors are often larger at diagnosis. Insulinomas > 9 cm are sometimes referred to as ‘giant insulinomas’, of which 50% have distant metastases at presentation (Ueda et al. 2016).
In contrast to non-functioning PanNETs, tumor grade based on mitosis count per high power field or Ki-67 staining index is not univocally associated with aggressive behavior (Alkatout et al. 2015, Yu et al. 2017, Henfling et al. 2018, Andreassen et al. 2019, Sada et al. 2021). Importantly, even grade 1 tumors may show aggressive behavior (Wild et al. 2011, Hackeng et al. 2020); therefore, tumor grade cannot reliably be used clinically for excluding aggressive behavior. Other clinicopathological variables that have shown prognostic value for non-functioning PanNETs, like lymphovascular or perineural invasion, have not been studied for insulinoma.
Several immunohistochemical markers may be of use in separating indolent from aggressive insulinomas. Diffuse cytoplasmic insulin expression is seen in 90–100% of indolent insulinomas (Roth et al. 1992, Azzoni et al. 1998, de Sa et al. 2007, Andreassen et al. 2019). Interestingly, aggressive insulinomas often only have sporadic or focal insulin expression, and some studies have reported cases lacking immunohistochemical insulin expression, although this might be a sampling effect in larger tumors (de Sa et al. 2007, Yu et al. 2017, Andreassen et al. 2019). In line with these findings, decreased INS mRNA expression (relative to normal beta-cells) was seen in aggressive vs indolent insulinomas (Henfling et al. 2018). Aggressive insulinomas are multihormonal in 50% of cases compared to 25% of indolent insulinomas (Kapran et al. 2006), and glucagon is expressed more often in aggressive cases (de Sa et al. 2007, Andreassen et al. 2019).
Several other studies have found aggressive insulinoma to show transcription of non-beta-cell genes or lack of typical beta-cell markers. By gene expression profiling, SERPIN1A, coding for alpha-1-antitrypsin, was shown to be upregulated in aggressive insulinomas, which was confirmed by immunohistochemistry (de Sa et al. 2007). Normal beta-cells do not express alpha-1-antitrypsin, but glucagon-producing alpha-cells and somatostatin-producing delta cells do (Bosco et al. 2005). Pancreatic beta-cells also express GLP-1R, an important regulator of beta-cell proliferation (Cornu et al. 2010). Most indolent insulinomas express GLP-1R, while aggressive insulinomas and non-functioning PanNETs often do not (Cases et al. 2014, Waser et al. 2015), which is concordant with isotope-labeled exendin-4 (GLP-1 agonist) nuclear imaging studies (Wild et al. 2011, Sowa-Staszczak et al. 2013). Interestingly, the proliferative effects of GLP-1 on beta-cells were shown to depend on IGF-2 and IGF-1R expression (Cornu et al. 2010). In contrast to indolent cases, aggressive insulinomas or insulinomas ≥ 2 cm have decreased immunohistochemical protein expression of IGF2, cytoplasmic IGF1-R and INSR (Henfling et al. 2018), consistently showing that aggressive behavior is associated with independence or inactivation of typical beta-cell pathways.
Genetic insights
Most insulinomas have a unique mutational profile compared to non-functioning PanNETs (Table 1). Indolent insulinomas have a median of eight somatic coding mutations (IQR 5–14), based on combined data from exome sequencing studies (Supplementary Data 1, see section on supplementary materials given at the end of this article) (Cao et al. 2013, Cromer et al. 2015, Scarpa et al. 2017, Wang et al. 2017, Qi et al. 2018). Only few aggressive insulinomas have been sequenced and showed similar numbers of mutations in coding genes compared to indolent cases (Scarpa et al. 2017, Wang et al. 2017). Early studies failed to find significant numbers of MEN1 gene mutations (Zhuang et al. 1997, Cupisti et al. 2000, Jonkers et al. 2005), commonly seen in non-functioning PanNETs (Scarpa et al. 2017, Hong et al. 2020). Indeed, recent studies with large cohorts confirm that MEN1 mutations are not major drivers in insulinoma tumorigenesis (Wang et al. 2017, Hong et al. 2020). In 2013, Cao and colleagues discovered that 20% of insulinomas harbor hotspot mutations (T372R) in the transcription factor Yin Yang 1 (YY1) gene, a mutation that is almost exclusively found in insulinoma (Choi et al. 2011, Cao et al. 2013). Wild type YY1, expressed in normal beta-cells, acts as a transcriptional activator of the INS gene, possibly by directly binding to the enhancer regions or through increased expression of CACNA2D2 and ADCY1, which play a role in Ca2+ dependent insulin secretion (Cromer et al. 2015, Liu et al. 2022). YY1 T372R mutation has no prognostic value, as similar proportions were found in indolent and aggressive insulinomas (Cao et al. 2013, Cromer et al. 2015, Lichtenauer et al. 2015).
Somatic alterations and telomeric phenotypes in indolent and aggressive sporadic insulinoma.
| Indolent | Aggressive | |
|---|---|---|
| Cases (%) | Cases (%) | |
| YY1 | 92/396 (23%) | 6/35 (17%) |
| MEN1 | 10/198 (5%) | 1/9 (11%) |
| ALT-phenotype | 3/41 (7%) | 5/7 (71%) |
| ATRX or DAXX | 3/212 (1%) | 5/10 (50%) |
| CDKN2A loss/mutations | 1/141 (1%) | 1/5 (20%) |
| ZZEF1 | 1/47 (2%) | 1/2 (50%) |
| PTEN | 0/74 (0%) | 1/4 (25%) |
| ATM | 4/73 (5%) | 0/4 (0%) |
| AHNAK2, ARHGAP35, GAK, H3F3A, MYH15, VPS13C, ZCCHC6, ZIC4, TSC2, KDM6A, STAG2, DOCK4, EVA1C, FRG1 | At least two cases described (but in < 5% of cases) | No mutations reported, but few cases tested |
Based on various modalities, including Sanger and next-generation sequencing, immunohistochemistry and fluorescence in situ hybridization (for all separate studies see Supplementary Data 1) (Zhuang et al. 1997, Cupisti et al. 2000, Cao et al. 2013, Cromer et al. 2015, Lichtenauer et al. 2015, Sadanandam et al. 2015, Scarpa et al. 2017, Wang et al. 2017, Chan et al. 2018, Parekh et al. 2018, Qi et al. 2018, Di Domenico et al. 2020, Hackeng et al. 2020, Hong et al. 2020, Song et al. 2021)
A recent study found that indolent insulinomas without significant chromosomal copy number alterations (Ins-Neutral) were enriched for YY1T372R, showing mutations in 17/39 cases (59%). In contrast, YY1T372R mutations were seen in only 4/55 (7%) indolent insulinomas with amplifications (Ins-Amp) (Hong et al. 2020).
Indolent vs aggressive insulinomas
The low incidence of aggressive insulinomas has resulted in few data on genetic alterations in these tumors. The first evidence of biological differences between indolent and aggressive insulinomas was discovered by comparative genomic hybridization (CGH). Loss of chromosome 6q and gains of 12q, 14q and 17pq were associated with aggressive insulinoma. Chromosomal instability (CIN), defined as an arbitrary number of gains and losses, was the best predictor of aggressive behavior, outperforming tumor size and grade in a series of 44 indolent and 18 aggressive insulinomas (Jonkers et al. 2005). Using an array-CGH, the results were replicated by the same group. Moreover, the number of telomeric losses was also associated with aggressive insulinoma. CIN was not due to mutations in TP53 (Jonkers et al. 2006).
Recently, in a small series of insulinomas, we presented a possible cause of this observed CIN (Hackeng et al. 2020). Alternative lengthening of telomeres (ALT) was seen in 4/5 aggressive insulinomas, while absent in 30 indolent cases. ALT is a mechanism of telomere lengthening independent of telomerase and strongly associated with mutations in Alpha-Thalassemia/mental Retardation, X-linked (ATRX) and Death Domain Associated Protein (DAXX) in PanNETs (Heaphy et al. 2011). The ALT phenotype can be determined by various techniques, including a clinically feasible telomere fluorescence in situ hybridization (FISH) (Fig. 1). Moreover, mutations in ATRX and DAXX can reliably be determined by showing immunohistochemical loss of ATRX or DAXX protein expression (Heaphy et al. 2011) (Fig. 1). ATRX/DAXX work together as histone chaperone complex to deposit the stabilizing histone variant H3.3 at repetitive DNA sequences, such as telomeric regions. Loss of this function results in the destabilization of telomeric regions, telomere maintenance by homology-directed telomere recombination or synthesis, and widespread CIN (Marinoni et al. 2014, Heaphy & Singhi 2022).
Prognostic markers in two aggressive insulinoma cases. Pictures were made at 20× magnification. (A)–(C) Primary aggressive insulinoma (previously published as metastatic insulinoma case 3 (Hackeng et al. 2020)). (D)–(F) Liver metastasis of aggressive insulinoma (previously published as metastatic insulinoma case 5 (Hackeng et al. 2020)). (A)/(D) Hematoxylin and eosin stain. (B)/(E) Strong ARX expression in 100% of tumor nuclei. (C) Loss of immunohistochemical DAXX expression in tumor nuclei, note retained stromal expression. (F) Telomere fluorescence in situ hybridization showing ultra-bright telomeric foci in tumor nuclei (white arrowheads), diagnostic for the alternative lengthening of telomeres phenotype.
Citation: Endocrine-Related Cancer 30, 5; 10.1530/ERC-22-0321
In the five patients with aggressive insulinoma, only three patients were tested for ATRX/DAXX mutations by immunohistochemistry, of which one case had DAXX loss. None of the indolent insulinomas showed ALT or ATRX or DAXX loss. Moreover, CDKN2A loss was found in one aggressive insulinoma (Hackeng et al. 2020), an association which was reported before (Bartsch et al. 2000).
For the few additional aggressive insulinomas described in the literature, four out of seven cases tested had ATRX or DAXX mutations (Sadanandam et al. 2015, Scarpa et al. 2017, Wang et al. 2017, Chan et al. 2018, Lawrence et al. 2018, Di Domenico et al. 2020), and one out of two cases tested displayed ALT (Scarpa et al. 2017, Di Domenico et al. 2020). ATRX or DAXX mutations/protein loss and ALT are extremely rare in indolent insulinomas (Table 1). Moreover, some of the reported indolent insulinomas with ALT or ATRX/DAXX loss had adverse histopathological factors, questioning the correct classification of these cases as indolent insulinoma. Scarpa et al. found that two out of seven indolent insulinomas have ALT. One of these was the only case with extra-pancreatic spread classified as ENETS T4 tumor. The other measured 40 mm had positive resection margins and unknown lymph node status (Scarpa et al. 2017).
Epigenetic insights
Recent advances in profiling the epigenetic landscape of non-functioning PanNET have led to new insights in our understanding of insulinoma biology. Recently, ChIP-seq analyses in non-functioning PanNET identified subgroup ‘A’ and ‘B’ which showed differential enhancer acetylation of lysine 27 of histone 3 for ARX and PDX1 loci, corresponding with differential immunohistochemical ARX and PDX1 expression, and mRNA similarities with alpha- and beta-cells, respectively (Cejas et al. 2019). DNA-methylation profiling and RNA sequencing showed an association between mutations in either ATRX, DAXX or MEN1 (ADM-mutant) with ‘alpha-like’ characteristics in non-functioning PanNET (Chan et al. 2018).
Indolent vs aggressive insulinomas
In the previously mentioned series of insulinoma that identified ALT as a marker of aggressive behavior, ARX/PDX1 immunohistochemistry was also assessed (Hackeng et al. 2020) (Fig. 1). As ARX is not expressed in beta-cells (but is expressed in alpha-, gamma- and epsilon-cells) and PDX1 is not expressed in alpha-cells (but is expressed in beta-, gamma-, delta- and epsilon-cells) (Baron et al. 2016, Muraro et al. 2016), we expected all insulinomas to be PDX1+/ARX−. Surprisingly, all aggressive insulinomas had ARX expression with or without PDX1 expression, while indolent cases showed the expected PDX1+/ARX− phenotype (Hackeng et al. 2020). This suggests a ‘non-beta’ like differentiation of aggressive insulinoma. Most ARX-positive cases also had ALT, similar to non-functioning PanNETs.
Several other studies have addressed the epigenetic landscape of insulinomas. Sadanandam and colleagues described an ‘insulinoma-like’ subgroup of neuroendocrine tumors, consisting of mostly insulinomas and, interestingly, a few non-functioning PanNETs (Sadanandam et al. 2015). Insulinoma-like tumors lacked ATRX/DAXX mutations and generally expressed PDX1. The single clinically aggressive insulinoma clustered with mostly non-functioning PanNETs in the ‘metastasis-like primary’ group and was ATRX mutated. Di Domenico et al. used an elegant phylo(epi)genetic analysis on whole genome methylation data and found that tumors in alpha-like and beta-like groups have high degrees of similarity with their normal cell counterparts, while an intermediate group had some similarities to alpha-cells and weak similarity to beta-cells (Di Domenico et al. 2020). For cases with clinical information or TNM (tumor, node, metastasis) staging, including previously published methylation data by Scarpa et al., 9 out of 13 insulinomas were considered ‘beta-like’ and all were indolent. Four out of 13 insulinomas were considered ‘intermediate’ or ‘alpha-like’, of which three cases had ATRX/DAXX mutations, and two cases had already shown aggressive behavior like lymph node/distant metastases (Scarpa et al. 2017, Di Domenico et al. 2020, Lakis et al. 2021). Boons et al. determined subtype by PDX1 locus methylation in four indolent and one aggressive insulinoma and show the indolent cases clustered with normal beta-cells while the aggressive insulinoma clustered with normal alpha-cells (Boons et al. 2020). Chan and colleagues found one aggressive and two indolent insulinomas in their study. As they made their data publicly available, an aggressive ADM-mutant insulinoma was classified as ‘A or alpha-cell like’ or ‘intermediate-type’, depending on the classification used, while the indolent cases were classified as ‘B or beta-cell like’ (Chan et al. 2018, Boons et al. 2020, Di Domenico et al. 2020). All three insulinomas had PDX1 mRNA expression, while only the aggressive case expressed high levels of ARX (Chan et al. 2018).
Conclusions
Although indolent and aggressive insulinoma are two different presentations of the same clinically defined disease, recent insights in our understanding of the tumorigenic alterations and (epigenetic) differentiation show significant differences that correlate with distinctive clinicopathological cell-of-origin-related characteristics (Table 2 and Fig. 2).
Features distinguishing indolent from aggressive insulinomas.
| Indolent | Aggressive | |
|---|---|---|
| Clinical | Long history of hypoglycemia Lower levels of insulin, pro-insulin and c-peptide |
Short history of hypoglycemia Higher levels of insulin, pro-insulin and c-peptide |
| Pathological | Small (usually < 2 cm) | Large (> 2–3 cm) |
| Immunohistochemical | Insulin diffusely positive Few tumors multihormonal Alpha-1-antitrypsin may be positive GLP-1R positive ATRX/DAXX positive |
Insulin focally positive Often multihormonal Alpha-1-antitrypsin usually positive GLP-1R can be negative ATRX/DAXX can be negative |
| Genetic | ATRX/DAXX wildtype Copy number neutral/few gains ALT negative |
ATRX/DAXX may be mutated Chromosomal instability common ALT often positive |
| Epigenetic | Beta-cell type Surrogate IHC: ARX−, PDX1+ |
Intermediate/alpha-cell type Surrogate IHC: ARX+, PDX1 + or − |
ALT, alternative lengthening of telomeres; IHC, immunohistochemistry.
Genetic and epigenetic profile of indolent and aggressive insulinoma. ALT, alternative lengthening of telomeres; CIN, chromosomal instability.
Citation: Endocrine-Related Cancer 30, 5; 10.1530/ERC-22-0321
Indolent insulinomas usually become clinically apparent when small (typically < 2 cm) due to abundant insulin production leading to hypoglycemia. They remain close to their presumed cell of origin, the beta-cell, evidenced by epigenetic and transcriptomic profiling, and diffusely express typical beta-cell proteins, like insulin, GLP-1R and PDX1.
Aggressive insulinomas, on the other hand, only show symptomatic insulin production when large (most often > 3 cm) or giant (> 9 cm). The period of experiencing symptoms may be shorter than for indolent insulinomas, and fasting may result in shorter onset hypoglycemia. Aggressive insulinomas regularly express proteins not encountered in normal beta-cells, like ARX, glucagon and alpha-1-antitrypsin. These aggressive tumors harbor mutations of ATRX/DAXX and the associated ALT phenotype and CIN are often seen. These alterations are virtually absent in indolent insulinomas. Surgery often does not cure disease, as cases have often metastasized locally or to distant organs.
The finding of ARX expression, ALT and large tumor size in our small series of aggressive insulinomas supported the notion that aggressive insulinomas might originate from (transdifferentiated) non-functioning PanNETs, in which these markers are common (Scarpa et al. 2017, Hackeng et al. 2020). This theory has been suggested before in the literature on giant or malignant insulinomas (Callacondo et al. 2013, Yu et al. 2017). By definition, giant insulinomas have been clinically ‘non-functional’ for a period of time due to their large size. Moreover, several cases of non-functioning PanNET progressing into aggressive insulinomas over time have been published (D'Arcangues et al. 1984, Sugiyama et al. 2010, Vashi et al. 2011, Callacondo et al. 2013, Yu et al. 2017, Juhlin et al. 2019, Keen et al. 2020). The subject was recently extensively reviewed, which concluded a likely non-functional origin of aggressive insulinoma based on natural history, biochemical profile and ARX/PDX1 gene expression (Yu 2020).
It is unknown why aggressive insulinomas (which might be transdifferentiated non-functioning PanNETs) become functional only when large. We previously hypothesized that either inherent low-level insulin production combined with increased tumor mass (e.g. the presence of widespread metastases) or rapidly acquired insulin production cause these tumors to reach the functional threshold for symptomatic hypoglycemia (Hackeng et al. 2020). Moreover, it is unclear if the insulin production is due to a subpopulation of differentiated beta-like cells or might be due to cells with ‘intermediate’ differentiation as seen in ADM-mutant non-functioning PanNETs (Fig. 2) (Di Domenico et al. 2020). As some aggressive insulinomas show scattered immunohistochemical PDX1 staining while others were diffusely positive, both might be true for a proportion of cases (Hackeng et al. 2020).
To conclude, if an insulinoma > 2 cm is encountered in the clinic, it seems prudent to perform ATRX/DAXX immunohistochemistry or sequencing and/or a telomere FISH if available. ARX expression can be useful to identify non-beta-cell differentiation. Additionally, other immunohistochemical markers like insulin, glucagon, PDX1, alpha-1-antitrypsin and GLP-1R may also have value to further assess alpha and beta-cell differentiation. If the findings are suggestive of aggressive behavior, this might warrant more intense follow-up, similar to non-functioning PanNETs. Ideally, prospective studies should be performed to determine if a change of therapy choice informed by these markers improves prognosis.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-22-0321.
Declaration of interest
The authors declare no potential conflicts of interest.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Acknowledgements
We would like to thank Prof. Sunita Agarwal (on the cohort published in Parekh et al. 2018) and Prof Yuan-Jia Chen (on the cohort published in Song et al. 2021) for providing information to make the separate description of genetic alterations in indolent and aggressive sporadic insulinomas possible.
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