1 INTRODUCTION

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the presence of benign tumors in various tissues in the body. The most commonly involved organs are the skin, brain, kidneys, lungs, eyes, and heart. Although TSC was once thought to be a very rare condition, the incidence is now known to be 1:6000 live births (Krueger et al., 2013; Northrup et al., 2013). The etiology of TSC involves inactivating mutations in two genes, TSC1 and TSC2, which encode for hamartin and tuberin, respectively. These two genes normally suppress the action of the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is an essential regulator of cell growth and metabolism through the modulation of protein and lipid synthesis, lysosome biogenesis, and autophagy (Takahara et al., 2020). In TSC, the downstream activation of mTORC1 leads to dysregulated cell growth in various tissues. Although the majority of TSC associated tumors are benign, for reasons that are not understood, a subset of TSC patients develop malignant tumors (Amin et al., 2017). According to Mortaji et al. (2018), patients with TSC have an 18-fold overall increased risk of malignancy compared with the general population. Furthermore, TSC is known to be associated with malignancies such as renal cell carcinoma and chordoma (Lam et al., 2018; McMaster et al., 2011). In recent years, an association has also been made between TSC and another rare and potentially malignant tumor, the pancreatic neuroendocrine tumor (PNET) (Arva et al., 2012; Bombardieri et al., 2013; Díaz et al., 2012; Dworakowska & Grossman, 2009; Francalanci et al., 2003; Koc et al., 2017; Larson et al., 2012; Mehta et al., 2019; Mortaji et al., 2018; Verhoef et al., 1999). Despite multiple case studies and a large review of TSC patients with PNETs, there remains limited information in the literature regarding other pancreatic lesions that may occur in TSC. Our data demonstrate that patients with TSC may have varying types of pancreatic involvement including intraductal papillary mucinous neoplasms (IPMN). IPMNs are grossly visible (≥1 cm), mucin-producing, predominantly papillary or rarely flat epithelial neoplasms that arise in the main pancreatic duct and/or its branches (Gallucci et al., 2012). In this study, we examine a cohort of TSC patients with various types of pancreatic involvement in order to further characterize pancreatic involvement in TSC with a special focus on PNETs due to their potential for metastasis.

In the general population, PNETs have a reported prevalence of 0.003% (Dasari et al., 2017; Lawrence et al., 2011; Yao et al., 2008). Previous literature suggests that the prevalence of functional and nonfunctional PNETs in patients with TSC ranges from 1% to 9% (Eledrisi et al., 2002; Koc et al., 2017; Larson et al., 2012). Interestingly, more recent publications are on the higher end of the range likely due to increased awareness and recommendations for increased surveillance of abdominal imaging in the TSC population. Surgical resection is the current recommendation for management if the PNETs are hormone secreting (functional) or nonfunctional and >2 cm in size (Cejas et al., 2019; Larson et al., 2012; Halfdanarson et al., 2008). 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.

2 MATERIALS AND METHODS

A retrospective review of patients meeting criteria for a definite diagnosis of TSC seen at the Herscot Center for TSC at the Massachusetts General Hospital identified 28 patients (13 males and 15 females) with associated pancreatic lesions. A single radiologist, with 2 years of subspecialty abdominal imaging experience at Massachusetts General Hospital reviewed 102 cross-sectional imaging studies including contrast enhanced tomography (CT) and magnetic resonance imaging (MRI) scans of the 28 patients. Five patients had imaging performed at an outside hospital, and 23 patients had imaging performed at MGH. All 28 patients had scans that were performed under concordance with the current abdominal imaging protocol for patients with TSC; four patients had further imaging that specifically focused on the pancreas following the identification of a pancreatic lesion on surveillance imaging. The scans were performed over a period of 15 years (from 2006 to 2021). Lesion size was reported based on the greatest diameter. For each patient, we determined when the pancreatic lesions were initially detected on imaging. We then reviewed imaging from two prior scans to ensure that we were able to capture the rate of change of the lesion over time. For patients who proceeded to surgery, we reviewed all relevant abdominal imaging from the time of detection up until the resection. Two of the patients that proceeded to surgery did not have pre-operative imaging available in their medical records for review. For patients who had a lesion resected, we reviewed imaging following their resection to assess for recurrence. Additionally, we reviewed operative reports to assess for complications. Pathology reports were reviewed to determine the final characteristics and size of the lesions. Furthermore, we reviewed perioperative and post-operative medical records to determine if patients required exogenous insulin following surgery.

3 RESULTS

Of the 637 patients meeting diagnostic criteria for TSC seen from 2006 to 2021, pancreatic lesions were reported in 28 patients (13 males and 15 females) ranging in age from 4 to 67 years old; imaging was available for all 28 patients; however, two of the patients who proceeded to surgery did not have any pre-operative imaging available for review. Nineteen of the patients had a single lesion in the pancreas; seven had multiple lesions. Of those patients with a single lesion, eight of the lesions were solid-appearing; eleven were cystic. Of the seven patients with multiple lesions, five patients had multiple cystic lesions; two patients had multiple solid-appearing lesions. Of the patients with a single lesion, eight patients had the lesions noted in the tail, five in the body, five in the head, and one in the neck. Five patients had lesions with evidence of communication with the main pancreatic duct on imaging (Table 1).

Thirteen of the 28 patients with pancreatic lesions underwent surgical resection (Table 2). Six were female; 7 were male. Two of the patients had two tumors. All 15 of the specimens were identified as pancreatic neuroendocrine neoplasms on histopathological examination. Six were grade 1 (low grade) and four were grade 2 (intermediate grade) based on the 2010 World Health Organization (WHO) classification. There were no grade 3 (high grade) tumors identified in the cohort. Four of the pathology reports did not specify the grade of the tumor. Eleven of the patients had no documented evidence of metastasis to the lymph nodes. For two of the patients, the pathology report did not mention lymph node evaluation. The average tumor size on final surgical pathology was 2.74 cm (range 0.70–5.10 cm). Of those patients with a single PNET, seven were located in the tail of the pancreas and four in the body. One patient had two tumors; one in the neck and the other in the body. Another patient also had two tumors; one in the body and the other in the tail.

The average age at the time of surgery was 26.2 years of age (range 4–67 years). Eight of the resections were performed laparoscopically; five performed through laparotomy. There were no serious complications reported for any of the patients. Two patients had complications after having an operation at an outside hospital. One patient was discharged home with a drain for a low volume pancreatic leak; the drain was removed 5 weeks post-operatively. The other patient had a postoperative fluid collection and pancreatitis which required US-guided drainage of a left abdominal fluid collection on postoperative day 6. Both patients with complications had a laparotomy. Notably, none of the 13 patients required exogenous insulin following the resection. Twelve of the patients who underwent resection have not had evidence of disease recurrence with follow up ranging from 5 months to 22 years. One patient had a recurrence of nonfunctional PNET identified on imaging 33.8 months after resection. The patient was subsequently lost to follow up.

All of the 13 PNETs were nonfunctional. Eleven were identified through surveillance imaging. The other two were identified because of back pain and incidentally due to biliary colic. Of the 13 patients with confirmed TSC-associated PNET, 7 had undergone genetic testing. Five patients had a pathogenic TSC2 variant and two a TSC1 pathogenic variant. An additional patient has not undergone genetic testing themselves, but has a family history of TSC with an identified TSC1 mutation.

4 DISCUSSION

The spectrum and natural history of pancreatic involvement in TSC has not been well characterized and surveillance and treatment recommendations are not available. Our retrospective review identified 28 of 637 TSC patients with solid and cystic pancreatic lesions, suggesting that the pancreas is involved in approximately 4.4% of patients with TSC. Some of the lesions appeared to communicate with the pancreatic duct, suggesting that they may be branch duct type IPMNs. The imaging interpretation was confounded by the retrospective nature of the study, as these lesions were identified on standard abdominal MRI sequences, and not those optimized for assessment of the biliary tree (e.g., MRCP); in the presence of small lesions, it can be difficult to ensure a true communication to the pancreatic duct is present although it is highly probable that these were IPMNs. In the general population, branch duct type IPMN are considered for surgical resection if patients develop symptoms, a nodule, main duct dilation, or a size >3 cm (Lee et al., 2005; Sugiyama & Atomi, 1998). In our patient population, none of the patients with lesions that are suspicious for IPMN have undergone resection to date. Further investigation of these lesions may be indicated given the potential for these lesions to progress from low-grade dysplasia to high-grade dysplasia to invasive cancer in the general population (Lim & Allen, 2019). Additionally in our cohort, there appeared to be some patients with small cystic lesions in the pancreas. Regarding management of all TSC-associated pancreatic lesions, we recommend that they be closely followed with routine surveillance imaging of the pancreas rather than limiting to a renal protocol. Surveillance of the pancreas can be achieved through abdominal MRI every 1–3 years, which is the current recommendation for surveillance abdominal imaging in patients with TSC. More is to be known about the course of these various other TSC-associated pancreatic lesions.

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. However, this explanation does not fully explain our increased prevalence given that Mowrey et al. used data from all TSC Centers of Excellence, who presumably also have extensive knowledge of TSC manifestations.

The prevalence of PNETs in this TSC series was 2.1% or 21,000 per 1,000,000. Although the malignant nature of PNET is debated, there are cases in the literature of metastatic PNET in patients with TSC (Díaz et al., 2012; Francalanci et al., 2003; Verhoef et al., 1999). Additionally, there is a published case report of mortality in a 33-year-old TSC patient with a nonfunctional PNET (Amin et al., 2017). Due to the documented metastatic potential and possibility of fatality of TSC-associated PNETs, it is imperative that TSC-associated pancreatic lesions with features consistent with PNET are followed closely and considered for surgical management.

Of note, TSC-associated PNET appears to occur at a much younger age than in the general population. In our TSC population, the average age of surgical resection is 26 years; however, in the general population the average age at diagnosis is 56 years (Vagefi et al., 2007). The youngest in our population was a 4-year-old with a well-differentiated PNET. The reason why TSC-associated PNET are identified at an earlier age is unclear. It is possible this is due to the recommended abdominal surveillance imaging recommended for patients with TSC. Also notable is that our cohort had two patients with PNET and underlying TSC1 mutation. Pancreatic involvement was once thought to be more closely associated with TSC2 mutations (Mehta et al., 2019). However, there are two recent case reports of PNET in patients with TSC1 mutations, suggesting that this manifestation is not unique to TSC2 mutations (Mehta et al., 2019; Mortaji et al., 2018). The higher prevalence of PNET in patients with TSC2 may be partly explained by the fact that TSC2 mutations are more common overall (Dabora et al., 2001; Jones et al., 1999).

In the general population, surgical resection of PNETs is considered if they are functional or nonfunctional and ≥2 cm (Belotto et al., 2019; Wong et al., 2018). However, there are currently no guidelines for the management of TSC-associated PNETs. It is difficult to guide management, because it is unclear if TSC-associated PNETs behave similarly to those in the general population. Overall, the risk does appear to be elevated compared with the general population, however, the absolute risk is still considerably low for patients with TSC. Further research is needed to better characterize the natural history of TSC-associated PNET. The current NCCN guidelines for treating PNETs in the general population recommend surgical intervention for tumors >2 cm in size (Shah et al., 2018). Our current clinical practice uses similar guidelines in patients with TSC-associated PNET.

Our data highlight that using radiologic characteristics alone, it is difficult to discern between benign cyst and PNET given that some of the PNETs appeared cystic on preoperative imaging. Therefore, we recommend that the decision be made based on size criteria similar to management in sporadic tumors. 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. In summary, surgical resection should be considered in TSC patients with lesions ≥2 cm with features concerning for PNET given that in our experience, the operations carry a low risk of complications and the surgical outcomes are favorable.

AUTHOR CONTRIBUTIONS

Leah M. Evans helped design the study, collected and analyzed data, and drafted the manuscript. Kennedy R. Geenen assisted with data collection and analysis, and also drafted the manuscript. Aileen O'Shea and Sandeep S. Hedgire collected and analyzed data for this project. Cristina R. Ferrone helped design the study. Elizabeth A. Thiele designed the study and supervised the project. All authors were involved in the revision and final approval of the manuscript.

CONFLICT OF INTEREST

None to declare.