Treatment of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia-Type 1(MEN1): Some Clarity but Continued Controversy

I. Overview MEN1

MEN1 (prevalence 1–10/100, 000) is the most important inherited pancreatic neuroendocrine tumor (pNET) syndrome causing up to 10% of pNETS including 20–25% of gastrinomas, 4–5% of insulinomas and 3–15% of NF-pNETS^{1, 2}. MEN1 is an autosomal dominant disorder classically characterized by neuroendocrine tumors of the parathyroid, pituitary, and pancreas, now known to be due to alterations in the protein, menin, caused by mutations in the MEN1 gene on 11q13^{1, 3}. Clinically patients develop primary hyperparathyroidism, (95–100%), functional (F-pNET)(20–80%) and nonfunctional (80–100%, symptomatic 0–13%) pancreatic endocrine tumors (NF-pNET) and functional/nonfunctional pituitary tumors (mean-55–65%[16–100%]^{1, 4–16}. The F-pNETs occur in MEN1 patients with a frequency of gastrinomas (54%-mean [range-20–61%)>insulinomas-18%[range-7–31%]>glucagonomas 3–4%[1–5%-range]>VIPomas, GRFomas, SSomas (<2%)¹. In addition these patients develop adrenal adenomas/carcinomas (27–36%), carcinoids (gastric [7–35%], lung, thymic [0–8%]), thyroid adenomas (0–10%) and more recently it is reported they also develop nonendocrine tumors of the skin (60–90%)(angiofibromas, collagenomas), CNS (0–8%)(meningiomas, ependymonas), and smooth muscle (1–7%) (leiomyomas, leiomyosarcomas)^{1, 16}. Characteristically MEN1 patients present with hyperparathyrodism as the initial manifestation of the disease, however in a number of more recent series up to 1/3 present with F-pNETs^17–19.

II. Unique Features of MEN1 NETs affecting management

pNETs in patients with MEN1 have a number of unique features, which have markedly complicated the therapeutic approach. First, NF-pNETs occur microscopically in 80–100% of MEN1 patients, are invariably multiple, throughout the pancreas, and it is estimated in only 0–13% of patients do they become symptomatic¹. In MEN1 patients with Zollinger-Ellison syndrome (ZES), it is now known the gastrinomas occur in 85–100% of patients in the duodenum, in the pancreas in 0–15%, and in the duodenum, frequently small (<0.5 cm), and associated with lymph node metastases in 40–60%, and in contrast to sproadic ZES patients, the duodenal gastrinomas in MEN1 patients are almost invariable multiple^{1, 20–23}. Insulinomas occur within the pancreas and may also be multiple^{1, 3, 16}. The result of this multiplicity of NF-pNETs and gastrinomas is that it is now generally recognized that these patients cannot be cured completely of all pNETs tumors without very aggressive surgical resections (complete pancreatectomy for NF-pNET). Patients with MEN1/ZES are only very rarely, if ever cured by pNET enucleation or local resection of the gastrinoma, even with detailed tumor localization studies [cross-sectional imaging, arteriography, gastrin hormonal gradient studies, and intraoperative duodenotomy/duodenal transillumination] and generally require a Whipple resection for cure^{2, 21, 22, 24–31}. In contrast, other F-pNETs (insulinomas, glucagonomas, etc.) are generally curable without extensive resections, but may recur^{1, 3, 25}.

III. Management controversies of MEN1 patients with NF-pNETs and gastrinomas

The features of MEN1 pNETs listed in the previous paragraph, as well as a number of other aspects of MEN1, have lead to considerable controversy on how to best manage pNETs in MEN1 patients. Whereas all agree that MEN1 patients with nongastrinoma F-pNETs (insulinomas, etc.) should undergo surgery, because of their high cure rate, this is not the case with MEN1 patients with NF-pNETs or gastrinomas^{1, 3, 25, 32, 33}. The fact that the most frequent p-NETs that occur in MEN1 patients (NF-pNETs, gastrinomas) are so often multiple, small in size, rarely curable without extensive resection, and increasing evidence suggest patients with small lesions (<1.5–2 cm) have a excellent prognosis without surgery in most cases, in itself has led to considerable difference in opinion on their management. In addition, when these points are combined with the fact that pNETs present approximately 10-years earlier in MEN1 than sporadic cases^{1, 18}, even occurring in patients < 20 years old¹⁹, this has led to considerable controversy on which patients should undergo surgery or continued observation. Additional points that complicate this decision is the fact that increasing evidence suggests that patients with MEN1 have an increased incidence of diabetes and glucose intolerance^{34, 35}. This is of particular concern, especially in younger patients undergoing extensive pancreatic resections, because the occurrence of glucose intolerance/diabetes is reported in 34 %¹², 10%³⁶, and 86%³⁷ of MEN1 patients undergoing a major pancreatic resection and in 17–25 % of any patients undergoing pancreaticoduodenectomy³⁸. Another unique issue in MEN1 patients which has not been studied, but can effect the approach to management of the pNETs in the future, is the potential importance of continued radiation exposure in MEN1 patients who require life-long monitoring²⁷. This becomes an issue because if these patients are followed, continued imaging surveillance is required. Endoscopic ultrasound (EUS), while highly effective for this purpose²⁷, is an invasive procedure which is done under general anesthesia in many countries/settings, and therefore other imaging modalities that allow serial assessment of changes in pNET size, would be of clinical useful, such as repeated cross-sectional imaging studies (MRI, CT scanning). These imaging modalities may miss small pNETs<1.5–2 cm in diameter, which in a number of studies, patients with these show no increased mortality from pNETs of this size^{33, 39–42}. Nevertheless, because imaging studies not involving radiation such as MRI, miss a significant number of small pNETs in MEN1 patients there is increased interest in more sensitive imaging studies such as ⁶⁸Ga-DOTATOC positron emission tomographic/CT imaging (⁶⁸Ga-DOTATOC-PET/CT) which involve radiation. This interest has especially increased with recent studies reporting for the first time prospective^43–45 and non prospective studies^{46, 47} demonstrating enhanced sensitivity/specificity for localizing NETs, including pNETs, in MEN1 patients, using ⁶⁸Ga-DOTATOC-PET/CT. Lifetime exposure to radiation may be a particular issue in MEN1 patients because basic science studies demonstrate that menin, the protein altered in patients with MEN1, is involved in DNA repair, cell cycle control and transcriptional regulation, and when there is a loss of menin activity, as occurs in MEN1 patients, cells become more sensitive to the effects of ionizing radiation as well as other cell damaging injuries^48–50. With ionizing radiation the cells with inactivated menin show defects in DNA repair, alterations in cell cycle checkpoint regulation, and failure of up regulation of DNA damage response proteins such as p21 after the injury^{48, 49}. Numerous studies have raised concerns about the use of imaging studies involving radiation in younger patients (without MEN1)^51–53, and whether younger MEN1 patients are at increased risk is unclear. These points raise controversies about when and how frequent these serial imaging studies should be used.

Recent guidelines from a number of organizations for the treatment of pNETs in MEN1 patients, including ENETs^{25, 32, 33}, NANETs⁵⁴ and the Endocrine society⁴², recommend a conservative approach to patients with MEN1/ZES or NF-pNETs with imaged pNETs <1–2 cm. This approach is in contrast to patients with sporadic ZES in whom surgery is recommended whenever safe and the possibility of cure exists^{25, 32, 55, 56}, but is similar to the approach increasingly being used in asymptomatic patients with sporadic NF-pNETs^57–59. All agree that it is important that these patients be regularly followed and evaluated for growth of the pNET. This approach is recommended because of many of these concerns raised above as well as a few additional concerns. These small NF-pNETs as well as the gastrinomas are frequently found in young patients with MEN1 who have a potentially long life expectance and without aggressive resection, neither patients with ZES/MEN1 or NF-pNETs are cured^{1, 24, 32, 33, 60–63}. Numerous studies demonstrate that pNET enucleation does not result in cure of MEN1/ZES patients^{1, 22, 24}, and although even though proximal pancreaticoduodenotomy (Whipple resection) will cure the ZES in MEN1 patients^{1, 26, 64}, it is not routinely recommended in patients with MEN1 because of the long-term potential complications^{26, 36, 64}. Also, in patients with NF-pNETs, because of the multiplicity of small adenomas, a total pancreatectomy would be required, which because of its morbidity, is not recommended^{1, 63}. Furthermore, a large GTE study of MEN1 patients reported that MEN1 patients with small NF-pNETs (<2 cm) have no increased mortality⁴¹. In another study of MEN1 patients with NF-pNETs followed over mean of 6.5 years, no growth in the pNETs was seen³⁷. Furthermore, in MEN1/ZES patients with pNETs <2 cm in diameter followed for up to 15 years without surgery, the survival was 100%²¹.

IV. Effect of natural history of NETs in MEN1 patients on the controversies of NF-pNETs and gastrinoma treatment and future treatment

Although the treatment approach outlined in the previous paragraph is recommended by almost all endocrine society’s guidelines, there are a number of findings that suggest that this approach will need to be modified in the future. First, MEN1 patients develop multiple endocrine tumors in different locations and in general the natural history of these, as well as the cause of death of MEN1 patients at present, is generally not clear^{15, 65}. On this subject there are few prospective studies with much of the information coming from pooled retrospective studies. These types of results are important to determine how aggressive treatment should be in a given patient with multiple NETs, which may not be able to be completely removed. As shown in Fig. 1, the natural history of MEN1 patients and causes of their death have changed significantly, especially over the last 25 years. ZES was the major cause of death up until the late 1980s, when effective medical therapies for the gastric acid hypersecretion became available. Although H₂-histamine receptor antagonists, the first effective medical therapy to control the gastric acid hypersecretion, were effective in the 1980’s, the gastric acid hypersecretion in MEN/ZES patients was more difficult to control than nonMEN1 patients, especially if the hyperparathyroidism was poorly controlled, requiring higher H₂-receptor antagonist doses and more frequent dosing^{60, 66–69}. Uniform control of acid secretion was not achieved until the availability of PPIs in the late 1980/early1900s which resulted in the ability, in all clinical settings, to control gastric acid hypersecretion in all MEN1/ZES patients, who could take oral medication⁷⁰. Similarly, increasingly effective treatments for the hyperparathyroidism to prevent its serious side-effects (renal failure, etc.), as well as pituitary tumors and hypersecretory states of other F-pNETs (insulinomas, etc.), have resulted in these becoming an uncommon cause of death in MEN1 patients^{15, 71} (Table 1). In contrast, death due to malignant NETs has become an increasingly important cause of death in MEN1 patients (Table 1, Fig. 1). In a recent prospective study and analysis of the literature of the death of patients with MEN1 from non- gastric acid hypersecretory causes (n=227)¹⁵, it was found that 2/3^rds of patients died of a MEN1 related cause and within this group the principal cause was death due to pNETs (63%) and death due to thymic carcinoids (especially in males)(22%)(Table 1, Fig. 1)¹⁵. Furthermore, the mean age of death of MEN1 patients was 55 years, which is similar to a number of other recent studies (51–50 yrs.), which is markedly shorter than the nonMEN1 population^{15, 71}. Thymic carcinoids were not well recognized as part of the MEN1 syndrome until the 1980’s, however they are the most aggressive NET in these patients, occurring primarily in men, and are becoming an increasing cause of death in current series. (Table 1, Fig. 1)^{15, 72, 73}. These results support the conclusion that if life expectancy is to be extended in MEN1 patients more effect treatment of the malignant propensity of NET is needed, particularly for pNETs and thymic carcinoids. An important point here is that the exact malignant NET causing death in MEN1 patients is not well studied. Because these patients can have multiple malignant NETs including gastrinomas, NF-pNETs, gastric carcinoids and in males, thymic carcinoids, which is responsible for the metastatic disease and tumor related death is rarely established. It will be of importance to resolve this issue as it could have a large effect on how aggressive to be in the treatment of a given possible malignant NET in a MEN1 patient.

Fig. 1.

Time course of the changes in the reported causes of death in various series of MEN1 patients. This figures is modified from² to include data on the recent effect of thymic carcinoids on survival. Data are from^4–15

Table 1.

Causes of death in patients with MEN1 from recent series ^(*)

Death due to:	% of deceased patients Mean (range)
I. MEN1 related
MEN1-related disease	60 [28–81]
pNET	38 [19–62]
ZES	20 [9–38]=38
Acid related	4 [0–11]
Gastrinoma related	10 [7–38]
Malignant pNET	31 [10–62]
Thymic carcinoid	8 [0–24]
Hyperparathyroidism	2 [0–5]
Pituitary tumor	0.8 [0–3]
Lung carcinoid/tumor	0.7 [0–5]
Gastric carcinoid	0.4 [0–10]
Other MEN1 related causes(†)	3 [0–9]
II. Non-MEN1 related	36 [6–72]
III. Unknown cause of death	4.5 [0–13]

^(*)Data from 9 series (1719 MEN1 pts-mean followup-10 yrs) reported since 1999^{11–13, 15, 71, 82, 83} listed in more detail in Table 12¹⁵.

^(†)Other MEN1 related deaths were two due to pheochromocytoma; 5 to adrenal disease; 2 to brain tumors; 6 patients with carcinoid tumors not specified; one to progressive meningioma; one to esophageal cancer with Barrett’s esophagus with dysplasia secondary to poor control of GERD in the past; two patients died from epenydmomas and one with a malignant melanoma.

In general, pNETs are slow growing in MEN1 patients, although one prospective study reported that 15% of MEN1/ZES patients have a pNET that demonstrates aggressive growth⁷⁴. While this is a lower percentage than seen in sporadic ZES patients where the proportion is 25%^{75, 76}, it nevertheless supports the importance of regular evaluations for possible progression. While the guidelines of different Endocrine Society’s all recommend following patients with NF-pNETs and MEN1/ZES with lesions <2 cm, it is not clear whether this alone will extend survival. Some evidence suggests it may. In the prospective NIH study of MEN1/ZES patients with pNETs<2 cm without surgery, there were no deaths in patients followed for up to 15 years²¹. Furthermore, in a recent retrospective analysis of 199 patients with MEN1 followed for a mean of 8 years, the mean age of the patients that died was 51 yrs., however, in the 70 patients who were managed medically without surgical resection (presumably because of pNETS<2cm), the mean survival age was 77 years and the tumor growth was 0.02 cm/year⁷⁷. These results suggest that following existing guidelines for managing MEN1 patients with NF-pNETs and MEN1/ZES may extend survival.

However, with the increasing importance of the management of pNETs to extend survival, the essential problem still remains on how to identify which patients with pNETs will develop aggressive disease, so that routine follow-up for years can be better tailored. While a few MEN1 genotype-phenotype correlations in pNETs related to their growth/malignant potential have been described [mutations in JunD, CHES1, truncating mutations in the N- or C- terminal regions of menin gene (exons 2,8,9) and the CDNK1B V109G polymorphism]^{12, 78–81}, as well various pNET pathological characteristics (proliferative indices, etc.) proposed to be potentially useful, they have not been studied prospectively and are not widely used. Furthermore, other important questions remain in the management of these patients related to the current guideline recommendations that will need to be studied and addressed. These include what imaging modalities to use, how frequently, what age to be screening, when should surgery be performed, what type of operation to perform, and how to follow the patients postoperatively. To extend survival in these patients each of these issues needs to be systemically addressed.