Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports

Abstract

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs.Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identified 16 individuals, nine males and seven females, with a median age of 18.0 years (interquartile range: −15.5 to 25.5). Just over half (56.3%, n = 9) of the patients provided results from genetic testing. Six had pathogenic variants in TSC2 whereas three had pathogenic variants in TSC1. The average age at PNET diagnosis was 15.0 years (range: 3–46 years). Almost all individuals were diagnosed with a PNET during routine TSC surveillance, 56.3% (n = 9) by MRI, 12.5% (n = 2) by CT, 25% (n = 4) by ultrasound, and 6.2% (n = 1) through a surgical procedure. Follow up after diagnosis involved 68.8% (n = 11) having serial imaging and nine of the sixteen individuals proceeding with surgical removal of the PNET. Eight individuals had a history of using systemic mTOR inhibitors. Tumor growth rate was slightly less in individuals taking an mTOR inhibitor (−0.8 mm/yr, IQR: −2.3 to 2.2) than those without (1.6 mm/yr; IQR: −0.99 to 5.01, p > 0.05).Conclusions: Nonfunctional PNETs occurred at younger ages in our TSC cohort and more commonly compared to ages and prevalence reported for the general population. PNETs in patients on systemic mTOR inhibitors had lower rates of growth. The outcome of this study provides preliminary evidence supporting the use of mTOR inhibitor therapy in conjunction with serial imaging as medical management for nonfunctional PNETs as an alternative option to invasive surgical removal.

Tuberous sclerosis complex‐associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes

“…Of the pancreatic lesions identified in our TSC population, the most common was PNET, occurring in 2.1% of our population. Our frequency appears higher than a recent study which estimated the frequency of PNET in TSC as 0.65% (Mowrey et al, 2021). It is unclear why the frequency in our population is higher, although this may be in part due to the high caseload of TSC patients at MGH and close clinicopathologic follow‐up such that referring clinicians and reporting radiologists have more personal experience of this particular entity and its association with TSC.…”

“…Recent data indicate that a small cohort of TSC-associated nonfunctional PNET on mTORi showed lower growth rates when compared with their non-mTORi counterparts (Mowrey et al, 2021).…”

“…A potential alternative to surgical resection is the use of mTOR inhibitors (mTORi). Recent data indicate that a small cohort of TSC‐associated nonfunctional PNET on mTORi showed lower growth rates when compared with their non‐mTORi counterparts (Mowrey et al, 2021). However, given the low risk of complications associated with laparoscopic resection, the surgical route may be preferred by some patients as opposed to long‐term therapy with mTOR inhibitor.…”

“…At this time, it is still unclear if the natural course of PNETs in TSC is similar to that in the general population. The largest review of PNET in TSC involving 40 patients was published in 2021, which recommended surgical intervention for tumors larger than 2.5 cm in diameter or rapidly growing tumors (Mowrey et al, 2021). In our study, we review the surgical outcomes of 13 TSC patients with previously resected nonfunctional PNETs in an attempt to guide future management of TSC‐associated PNETs.…”

Prevalence of thoracoabdominal imaging findings in tuberous sclerosis complex

“…Further, with the increasing use of mTOR inhibitors (mTORi) as disease-modifying therapy, manifestations of TSC beyond the hallmark manifestations of subependymal giant cell astrocytoma, angiomyolipomas, LAM, and epilepsy are increasingly relevant [ 15 – 21 ]. Indeed, rare findings such as pancreatic neuroendocrine tumors in TSC can also respond to mTORi treatment [ 22 ].…”