The primary modality for treatment of MEN1 patients with hyperparathyroidism is surgery. Because MEN1 is associated with multiglandular parathyroid disease, the surgical strategy must address all four glands. The options for surgical approach are a 3½-gland parathyroidectomy or a total four-gland parathyroidectomy with heterotopic autotransplantation of parathyroid tissue to the forearm. Routine partial cervical thymectomy is also recommended in patients with MEN1 to address a possible supernumerary or ectopic parathyroid gland within the mediastinum. Although the value of routine preoperative imaging in patients with MEN1 and hyperparathyroidism has not been defined, diagnostic localization with sestamibi scanning, ultrasonography, CT, or MRI may be particularly helpful in reoperative cases and patients with missed ectopic glands.
It is also important to remember that hypercalcemia aggravates hypergastrinemia, so patients with parathyroid disease should be treated surgically before or concomitant with gastrinoma resection. There is a much higher incidence of persistent or recurrent hyperparathyroidism (≤50% at 5 years) in patients after any appropriate surgical approach. MEN1 patients should optimally undergo their primary operation in centers of endocrine surgery excellence with availability of intraoperative PTH measurements, surgeon-directed ultrasonography, and capabilities for parathyroid cryopreservation.
The management of patients with MEN1-associated PNET remains controversial. The primary reason for this is that the natural history of these tumors is not completely understood; prognostic indicators of malignancy or propensity to metastasize are unknown at this time. There is general consensus that functional tumors should be removed surgically. It can be argued that symptoms of gastrinomas may be effectively controlled with proton pump inhibitors; however, the progression of the tumoral process with potential for metastases remains with medical treatment alone. Although a correlation between the size of the primary gastrinoma and the frequency of metastases involving the lymph nodes and liver has been reported,23 another study7 including all MEN1-associated pancreaticoduodenal neuroendocrine tumors, both functional and nonfunctional, failed to show a correlation between size of the largest tumor and regional or distant metastases. Surgical resection of gastrinomas is complicated by the fact that tumors are small, often multiple, and may be extrapancreatic, within the duodenal wall or even possibly as lymph node primaries. Most large studies have shown that surgical treatment of patients with gastrinomas in MEN1 rarely have long-term normalization of their gastrin levels.24 However, owing to the possibility of decreasing metastatic disease in these patients, we recommend surgical exploration; duodenal exploration with intraoperative ultrasonography of the duodenal wall and pancreas; resection of gastrinomas; and an aggressive, extended regional lymphadenectomy in otherwise low-risk surgical candidates. Pancreaticoduodenectomy is appropriate for extensive or malignant gastrinomas in the duodenum or head of the pancreas.
Insulinomas require surgical intervention resection after the biochemical diagnosis has been established. Preoperative imaging may or may not accurately localize these tumors, which may be small (1 to 2 cm) and occult. The surgical approach consists of full mobilization and evaluation of the entire pancreas by visualization, palpation, and intraoperative ultrasound examination by an experienced operator (radiologist or surgeon). Enucleation is often the approach for these tumors, which are typically small and usually benign. Alternatively, a distal pancreatectomy may be performed for tumors within the tail of the pancreas; limited evidence suggests that this may reduce the risk of recurrence.
Patients with asymptomatic or nonfunctional tumors of the pancreas associated with MEN1 present the most challenging question regarding surgical management. Two alternative strategies have been proposed. First, surgical exploration in young asymptomatic patients with biochemical evidence of MEN1 may be performed. This may provide the benefit of decreasing the risk of malignant transformation or metastatic disease and may identify and treat disease well before it is clinically apparent.10 Alternatively, others advocate removal of PNETs that are functional, symptomatic, or large enough to be imaged with radiographic tests.
The operation for MEN1 PNET resection may be performed via a bilateral subcostal incision or an upper midline incision. An extended Kocher maneuver is performed to mobilize the duodenum and head of the pancreas, the greater omentum is taken down from the transverse colon, and the lesser sac is entered. To avoid bleeding, it is useful to ligate the middle colic vein at its origin in the superior mesenteric vein. The retroperitoneum is opened just below the inferior edge of the pancreas. Additionally, a medial rotation of the spleen and tail of pancreas may be performed for complete evaluation of the entire pancreas. Careful blunt dissection at each of these borders of the pancreas allows for palpation of the entire gland and surrounding lymphatic structures. Intraoperative ultrasonography is the gold standard localizing test and should be routinely used, preferably by an experienced operating surgeon. Smaller tumors of the pancreatic head are most commonly enucleated, and those of the body or tail may be managed with either enucleation or distal pancreatectomy. Splenic-preserving distal pancreatic is desirable when technically feasible. On the other hand, splenectomy may provide a more complete resection of lymph nodes along the splenic vessels in larger or malignant tumors of the pancreatic tail. Additionally, lymph nodes within the hepatoduodenal ligament, along the celiac axis, and posterior to the pancreatic head should be inspected and removed if suspicious.25
MEN1 neuroendocrine tumors located within the duodenum are removed surgically via longitudinal duodenotomy. After distending the duodenum with saline via the nasogastric tube, intraoperative ultrasonography and opening of the duodenum with digital palpation of the entire duodenal wall are performed. Enucleation of tumors smaller than 5 mm may be performed; the overlying mucosa is removed with the tumor. Full-thickness duodenal wall excision is required for tumors larger than this. The full-thickness excision site(s) and the duodenotomy are closed longitudinally in two layers.25 Some argue for a routine extended regional lymphadenectomy for MEN1 gastrinomas because they are frequently (80%) malignant with early lymph node metastases from even small primary tumors. Additionally, intraoperative hepatic ultrasonography may be beneficial to further investigate for metastatic disease involving the liver.
The most common functional pituitary tumors in MEN1 patients are prolactinomas. These tumors are most often managed medically with administration of dopamine receptor agonists such as bromocriptine or pergolide. However, surgical resection with a transsphenoidal approach may rarely be used for certain tumors. Operative treatment is most commonly indicated in large or rapidly growing prolactinomas that are unresponsive to medical therapy and in the other less common functional pituitary tumors mentioned above1 (Figure 21-2).
Algorithm for management of multiple endocrine neoplasia type 1 tumors by location: the pituitary (A), parathyroid (B), and pancreas (C). ACTH = adrenocorticotropic hormone; CRH = Corticotropin Releasing Hormone; PPI = proton pump inhibitor.