SO De ae Multiple Endocrine Neoplasia Type 1 Geoffrey B. Thompson, MD « William F. Young, Jr., MD ‘Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant-inberited disorder affecting tumorigenesis in at teas eight endocrine and nonendocrine tissues whose com- 3s were first recognized in the early 20th century. In 1943, Erdheim' described a patient with a pituitary adenoma and parathyroid hyperplasia discovered at autopsy. Gerste!* reported on a patient with acromegaly and a severe peptic ulcer diathesis in 1938, Wermer. in 1954, identified the autosomal dominant nature of the disease that bears his name (iermer's syndrome, now referred to as MEN 1). Children of an affected parent have a 50% chance of inberiting the disease predisposition that is noted to be highly penetrant. Larsson and associates,* in 1988, mapped the gene associ- sued with MEN I (MEN) tothe long arm of chromosome 11 (11q13). MEN/ is a tumor suppressor and encodes a widely expressed protein called menin. Clinical expression of the tenwsype requires not oniy inheritance of an MEN! germline mutation but also inactivation of the wild-type MEN/ allele derived from the unaffected parent.*” Mutations in the gene kead to widespread endocrine tumorigenesis. Approximately 90% of affected kindred members have mutations detectable by genetic testing, and the phenotype develops in virtually all individuals with germline mutations. Epidemiology and Clinical Presentation The twe prevalence of MEN 1 is likely underestimated; data ‘pgeat a prevalence of 0.2 to 2/100,000.* Major clinical anifestations in MEN 1 include the “3Ps”: primary hyper- Fuathyroidism (HPT) (95%), pancreatic endocrine tumors FETs) (50% to 75%), and pituitary tumors (30% to 55%). ession of the disease rarely occurs before 10 years of 2: and most often presents between 20 and 40 years of iE!" Two of the three major lesions must be present for Slinical diagnosis in probands. In family members of ‘hown MEN 1 kindreds, the presence of one major lesion is Pe able 16-1), Cinieal diagnosis is confirmed by sting All thee major clinical manifestations arise in less than 12% of affected patients." Any of these three clinical ‘manifestations may be the first component precipitating a diagnosis, but in most patients, primary HPT appears by the 3rd or 4th decades of life. Biochemical abnormalities can be detected decades before clinically overt symptoms become ‘manifest.’ For example, biochemical aboormalities may be noted in affected adolescents in their mid to late tecas when careful, egular screening is performed. Stodies have shown that delaying screening until clinical symptoms develop can be associated with locally advanced disease or distant metasta- tic disease in as many as 50% of patients with PETs."? Less common, but overrepresented, manifestations in MEN | include adrenocortical tumors,'*"” foregut carcinoid tumors,'*23 nonmedullary thyroid neoplasms (mostly follicular),** and a host of unusual cutaneous/mucosal or visceral abnormalities, including multiple subcutaneous and visceral lipomnas, multiple facial angiofibromas, hypomelan- otic macules, gingival papules, and collagenomas.*7” Rare associations with MEN 1 also include meningiomas, ependy- momas, pinealomas, renal cancers, rhabdomyosarcoma, leiomyosarcoma, and pancreatic ductal adenocarcinoma 574 The Molecular Biology of MEN 1 ‘The gene responsible for MEN 1 was identified in 1997" and is located on chromosome 11q13. MEN! spans 9 kb of genomic DNA and consists of 10 exons containing an 1830-base pair coding region. MEN/ encodes a 610-amino acid nuclear protein, referred to as menin. Menin is localized to tk: nucleus and interacts with the activating protein 1 transcription factor JunD and other proteins involved jn wanscription and cell growth regulation?+35 MENJ muta- tions are spread over the entire coding region (exons 2 to 10); approximately 50% are frameshift, 24% are missense, 20% are nonsense, and 7% are deletion or in-frame insertion mutations. MEN/ acts as a tumor suppressor gene, and ‘tumor development follows Knudson's “two-hit” hypothesis.” ‘Hence, individuals affected with MEN 1 inherit one MEN 673674 —— Endocrine Pancreas TA ses Ren eV ntsc Manifestations Prevalence (1) Major ("3 Ps") Primary hyperparathyroidism >95 Pancreatic/duodenal neuroendocrine 80-75 tumors Pituitary tumors Less Common ‘Adrenocortical tumors (functioning |. nd nonfunctioning; benign and {,imalignant) » Fotegut carcinoid tumors (bronchial, ‘thymio, gastrointestinal) ‘Nonmedullary thyroid neoplasms + Cutaneous/mucosal and visceral {abnormalities (multiple ipomas, facil angiofibromas, hypomelanotic *°fnacales, gingival papules, colagenomas) Diagnosis (cinical) of MEN 1: (1) two major manifestations present 'iqrproband or (2) one major manifestation in an atzisk member of ‘Yaixnown MEN 1 kindred. Confirmation is by genetic testing. ‘MEN 1 = multiple endocrine neoplasia type 1. 5 ea 30-55 allele with a germline mutation (the “first hit”), and tumori- genesis in specific tissues ‘then occurs after a second deleterious mutation (the “second hit”) is acquired in the remaining wild- type allele in a single cell.3” Such homozygous-inactivating MEN! mutations result in menin protein absence or trunca- tion, and neoplastic clonal expansion from that cell is then ini- tiated. Thus, the mechanism for tumor formation in MEN 1 involves loss of menin function in a tumor precursor cell. Unlike the RET protooncogene (associated with MEN 2), mutations in MENI do not clearly demonstrate significant ‘genotype-phenotype correlations." Recent studies have found preliminary data suggesting that mutation type or location within MEN] may be associated with clinical presentation.“ However, the limited data available regarding genotype-phenotype correlations do not currently warrant modification of clinical managemer ‘Several analytic approaches to identifying MEN/ mutations have been used, but most laboratories currently use direct DNA sequencing. The first step in the analysis of a sporadic case or & patient in a kindred with suspected or prover. MEN | is to identify the specific MEN/ mutation in germline DNA. Germline testing requires peripheral blood ftom an affected index case. In mest probands, a disease-causing mutation is identified. Because MEN/ somatic mutations are commonly found in endocrine tumors, tumor DNA is rarely useful in distinguishing germline mutations.*'*” It is estimated that more than 10% of germline MEN/ mutations arise. de novo and can subsequently be passed to future generations.“ Mutations in MEN/ are highly pperietrant; approximately 50% of mutation carriers are ‘symptomatic by 20 years of age, und nearly 100% are symp- tomatic by 60 years of age. Most large series have failed to find MEN/ germline mutations in 10% to 20% of index cases," likely reflecting undetected mutations, such as large deletions that are transparent 19 DNA. sequence analysis or mutations in another unknown gene. MEN muta- tional analysis is clinically available in atleast four molecu- Jar genetics laboratories in North rica, >. Who Should Be Considereg for Genetic Counseling and Testing? In general, genetic screening of presymy : is appropriate when early therapeutic nee indi, able for the tumors diagnosed, particularly Whe tag, ata preclinical stage. Although this has not been ©” © 2B, domized, prospective studies of MEN 1 paten "nm somewhat controversial, there is an increasing prt dence to suppor this contention, particularly wig” MEN I pancreatic neuroendocrine tumors, 34732 apt early recognition and intervention with reper jg Mh roid and pituitary neoplasia does not prolong sat ‘can reduce or prevent morbidity associated with tot overactivity and mass effect. on Clinical screening of at-risk family mem known MEN 1 kindreds should begin in meee when biochemical abnormalities can begin to be ga long before overt clinical manifestations and nese coccut Ifa familial mutation has been dented nega genetic test in an at-risk family member preclude meq for routine, lifelong biochemical screening and ix However, if a mutation is not detected in a proband, fury testing for MEN! mutations in at-risk family membersisnt indicated, and presymptomatic testing is not posite by direct DNA testing. In these cases, at-isk family ments must continue to be clinically monitored throughout tei lifetimes. Such families in which a mutation cant be ie tified may consider pursuing linkage analysis, a les dea method of tracking the disease allele through the family Because the process of genetic testing can be conpi cated, genetic counseling is recommended for all fami considering this option. Presymptomatic testing of ait family members can be emotional, and families may bent from a session with a genetic counselor. The genetic om selor acts as a guide, explaining the pros and cons of esis as well as aiding with interpretation of the resalts shouldbe family choose to proceed. Regarding testing of apparently sporadic MEN | patients, mutation screening should be considered in yous patients (<50 years of age) with HPT, particulary in the ‘with multigland disease or recurrent HPT in the absenee ol renal disease. Consideration should also be given 1016 patients with prolactinomas because up 10 14% of patients may actually have MEN 1. Testing is also apm0#7 ate for patients multiple pancreatic newroenlorie tumors (calcium levels should be checked in all ot with solitary PETs), patients with any MEN I lest ‘an adrenal lesion, and patients with bronchial and thy carcinoids (Table 75-2).!" Pituitary Tumors fs In MEN | kindreds, pituitary wmors are found i quently than primary HPT or PETs.* Signs a4 9 hp related to a pituitary adenoma are the initial cline Fg” tation of MEN 1 in up to 25% of “first in the 1 ge cases but in less than 10% of familial cases aY { TE Ce eco ok ae ead ‘jussk fly members in known MEN 1 kindreds Ag patients (<50 years) with multigland or recurrent "Pt (normal fenal function) pauents with prolactinomas (14% MEN 1) Patient with multiple PETS Pajents with any MEN 1 lesion and an adrenal k Fajents with bronchial or thymic carcinoids ion SS jaN 1 = multiple endocrine neoplasia type 1; PET = pancreatic Meferine tumor; HPT = hyperparathyroidismn osed prospectively.’® The estimated prevalence of pitu- jiay tumors in MEN | paticnts ranges from 10% to 60%.5°*% For example, in a series of 324 patients with MEN 1, pitu- jiary adenomas occurred in 197 (42%); mean age at diagno- fas Was 38 years (range. 12 to 83 years). In most MEN 1 patents, the pituitary tumors are macroadenomas (>10 mm) {Fig. 76-1). All subtypes of pituitary adenoma have been reported in MEN 1, but most frequently they are prolactino- ‘mas (60%). Patients may present with amenorthea/galact- hea in women, symptoms related to hypogonadism in men, and/or sellar mass effect symptoms.***** Less common gittary tumor subtypes in MEN | include somatotroph adenoma (acromegaly: ~25%), corticotroph adenoma (Cushing's syndrome; =5%), and clinically nonfunctioning, piuitary tumors (=10%). Monitoring for pituitary tumor development in the MEN I patient should include measure- iment of serum prolactin and insulin-like growth factor | as well as imaging of the pituitary by magnetic resonance imaging (MRI) every 2 to 3 years.” In patients with an abnormal pituitary MRI, hypothalamic-pituitary testing should te completed to characterize the type of the pituitary adenoma and its effects on the secretion of other pituitary bormones. Treatment of pituitary tumors in MEN 1 is guided ty the adenoma subtype and is identical to that in patients with sporadic pituitary tumors (Fig. 76-2). In addition, after ‘Muluple Endocrine Neoplasia Type 11 —— 675 successful pharmacologic or surgical treatment of the pi itary tumor, MEN 1 patients should continue to be evaluated with periodic pituitary tumor sercening since a second pitu- itary adenoma may arise from the remaining pituitary tissue. Primary Hyperparathyroidism Most MEN | patients develop hypercalcemia and primary HPT by the 4th decade of life.* Shepherd described cle- vated ionized serum calcium levels in 66% of patients younger than 25 years of age, 85% of patients between 25 ‘and 55, and 87% of patients older than 55 in a large cohort of MEN I family members.* Skogscid and colleagues described a mean age of onset of HPT at less than 19 years.'* TI in sharp contrast to patients with sporadic primary HPT who typically present in their 50s and 60s. Primary HPT is the initial clinical/biochemical manifes- tation of MEN 1 in 60% to 90% of patients, but the percentage may be as low as 30% in young at-risk patients who are screened. A serum factor mitogenic for parathyroid cells has been isolated in MEN 1 patients at levels 20 times those of normal subjects. Parathyroid mitogenic factor has far greater activity than any other measurable growth facior, and its activity has been quantified by in-vitro studies. Diagnosis ‘The diagnosis of primary HPT (Table 76-3) is dependent on demonstrating an inappropriaté immunometric parathyroid hormone (PTH) level in the face of an elevated ionized serum calcium level. Hypocalciuria due to benign familial hypocal uric hypercalcemia (BFHH) should be ruled out by calculating the calcium-creatinine clearance ratio: (24-hour urine calcium x serum creatinine) + (24-hour urine creatinine x serum calcium) ORE 76-1. Head MRI showing coronal (A) and sagittal (B) views of a prolactin-scereting pituitary my Yearold young man with maltiple endocrine neoplasia type | The patient presé nadenom (arrows) in an ly headaches, vision ted w a S-year history of da “sd delayed sexual maturation. The serum prolactin level was 6309 ng/ml. (normal, 1 to 1S ng/ml).676 — Endocrine Pancreas and by obtaining a detailed family history. Calcium-creatinine clearance ratios lower than 0.01 are indicative of BFHH. Localization Studies ‘Imaging clearly has a role inthe evaluation and management of patients with sporadic HPT, of whom 85% have a solitary Burka) Pere Os aR Rea mie Diagnosis Elevated ionized serum calcium level Inappropriate immunometric parathyroid hormone level Calcium-creatinine clearance ratio > 0.01, Indications for Surgical Intervention ‘Any symptomatic patient (nephrolithiasis, osteoporotic fractures, ot hypercalcemic crisis) ‘Total serum calcium level 2 1.0 mg/dL above the assay ‘upper limit of normal Nephrocalcinosis Hypercalciuria (>400 mg/24 hr) Decreased glomerular filtration rate by 230% for age- and. ‘sex-matched controls Worsening BMD (hip, radius, or spine) BMD T-score < -2.5 (2 SD from normal controls) Zollinger Ellison syndrome ‘MEN 1 = multiple endocrine neop roldism; GFR = glomerular fire density. Modified from Blezikian JP, Potts JT Jr, Fuleihan Gel, et al ‘Summary statement ffom a Workshop on Asymptomatic Primary ‘A Perspective for the 2ist Century. J Bone ia type 1; HPT = hyperparathy- ‘BMD = bone mineral Hyperparathyroidism: ‘Miner Rs 2001 17:2 FIGURE 76-2. Endonasal_transsphe pituitary surgery. (©Mayo, 2001.) "ida adenoma, rendering many of these patients candidates fora directed surgical approach. ©® The benefits of minimally inv sive parathyroidectomy in this subgroup of sporadic patens ents, however, the pathology is that of asymmetrical hyperplasia involving all parathyroid glands. Therefore, regardless of imaging, all glands musi be ‘explored and a transcervical thymectomy performed to rule out a supemumerary or ectopic gland, which is seen in as many as 20% of MEN 1 patients. Ima of multigland disease is often misleading and frequenly demonstrates only the dominant gland or glands.®? Sestamibi parathyroid scanning (SPS)* and percutaneous neck ultrasound* typically demonstrate only the dominant gland or glands in MEN | patients, that if treated as suc, will lead to persistent HPT for the unknowing and inexpet- enced surgeon. SPS may, on occasion, demonstrate an topic or supernumerary gland that may be easier to find wi preoperative knowledge of its whereabouts. These incvde hyperplastic glands located in the low anterior, middle, and desp posterior mediastinum; the undescended and intrathycisl glands; and the rare intrapharyngeal gland. Imaging doe. however, become essential in MEN I patients with recurent disease (discussed later). 7 Management of MEN 1 Hyperparathyroidism ‘The timing of parathyroidectomy is an important iss MEN | HPT involves all parathyroid tissue: thus, any Us ment surgeons provide is considered palliative.”*” Aemp's at eradicating all parathyroid tissue can result in a treatmentis far worse than the disease itself (permanent parahyoiism). In the past, 40% to 50% of MEN 1 Fis presented with nephrolithiasis; however, more only, patents are being explored for mild or relatively tic disease. In patients with mild disease, it is fiate to delay surgery until the serum calcium level @51 mg/dL. above the upper limit of normal.” Other indications include nephrolithiasis/nephrocalcinosis, hypercal- “ora, glomerular filtration rate decreased by 230% for age- fod gender-matched controls, worsening bone (hip, radius, or spine) mineral density, especially when the T-score is less than 555 (2SD from normal controls),”” and pancreatitis,”® Vague jeuropsychiatric disturbances and muscle weakness are less sgeifc indicators. MEN 1 patients with hypergastrinemia and jyperealcemia should undergo early parathyzoidectomy.”™# Hypercalcemia is a potent stimulus for gastrin secretion. Control of hypercalcemia can lower or even normalize serum in levels, often alleviating symptoms in MEN 1 patients with Zollinger-Ellison syndrome (ZES).° Operative Approach ‘AKocher collar incision is made. The incision is deepened down through the platysma, and superior and inferior sub- platysmal flaps are developed. The median raphe is divided aad the strap muscles are retracted laterally without divi- sion. The thyroid lobes are sequentially elevated, and all four parathyroid glands and any supernumerary glands are exposed, Most supernumerary glands are located in proxim- iy to the other glands or less often in ectopic locations. Transcervical thymectomy should be performed to rule out ‘supernumerary gland and to evaluate the thyinus for a car- cinoid tumor. Failure to identify a superior gland necessitates ‘mobilization of the superior thyroid pole by individually lig- ‘ting the superior thyroid artery and vein or their branches on tte thyroid capsule. This helps avoid injury to the external branch ofthe superior laryngeal nerve. Rotation of the upper pole upward and outward often brings the superior gland into view, Larger superior glands can migrate along the tracheoe- ‘sophageal groove, into the retroesophageal space, and down into the posterior mediastinum. These can usually be elevated into the wound with adequate exposure and gentle traction. Missing inferior glands should be sought within the thymus, tte carotid sheath, in an undescended location in front of the ‘crotid bifurcation, and just beneath the thyroid capsule, typ- ‘ally along its inferior pole. The rare ed superior Ferathyroid gland ean be located within the pharyngeal mus- Silaur. Intraoperative ultrasonography (IOUS) may be of ‘id in locating ectopic glands within the neck.*! ‘Once four glands have been identified and the transcervi- ‘al thymectomy has been performed, the Surgeon then pro- (2 With a subtotal parathyroidectomy-" Itis our preference agate behind an inferior gland ora ion thereof, de its size. Leaving an inferior gland or remnant makes ation safer because of the inferior gland's distance the recurrent laryngeal nerve. If a superior gland is ‘ch smaller or grossly normal compared to the rest, we (hilt consider leaving this as the remnant. The vascularized ‘Seman should be 50 10 60 mg in weight Pen onl be pepe peor to excising the other : to ensure its viability prior to completing the ‘Multiple Endocrine Neoplasia Type 1 —— 677 subtotal parathyroidectomy. If the remnant becomes devas- cularized, it should be removed and the other inferior gland trimmed. The remnant or remaining gland should be tagged with a nonabsorbable suture or preferably a metal clip. Additional parathyroid tissue should be cryopreserved or immediately autotransplanted (multiple small pieces total- ing 50 to 60 mg) into a small, infraclavicular, subcutaneous pocket. Despite earlier reports regarding the efficacy of cry- ‘opreservation®* and the viability of cryopreserved tissue in vitro studies,® we have used few of the hundreds of cryo- preserved specimens stored at Mayo Clinic. When used, rarely have these delayed autotransplants resulted in mean- ingfal restoration of normal parathyroid function. It is now this surgeon's (GBT) practice, when performing a subtotal parathyroidectomy, to transplant 50 0 60 mg of nonmalig nant parathyroid tissue into a chest wall subcutaneous pocket just below the clavicle. If the immunometric PTH level is 2 pmol/L (normal, | to 5 pmoVL) 24 hours postoperatively, the transplant is removed at the bedside. If the postoperative immunomettic PTH is below the evel of detection, the trans- plant is left in place. Time will ell whether grafi-dependent recurrences will be easier to detect and manage in this location, but itis thought to be the case. By placing the graft close to the deltopectoral groove, below the clavicle, selective venous sampling (SVS) (subclavian vein) can be used along with SPS and ultrasound to evaluate for graft-dependent recurrence. ‘Another option for managing MEN 1 primary HPT is total parathyroidectomy, transcervical thymectomy, and immediate forearm autotransplantation.***”% Autotransplantation is classically carried out by implanting 10 to 15 (1-mm) pieces of fresh tissue into multiple pockets of the nondominant, brachioradialis forearm muscle. Each site is marked with a fine, monofilament nonabsorbable suture for future refer- ence. The forearm skin incision should be made in a longi- tudinal fashion so as to avoid confusion with regard to a self-inflicted wound. Recurrence rates are extremely low fol- lowing total parathyroidectomy, but permanent hypoparathy- roidism rates can be unacceptably high" Later explantation is also more formidable with regard to intramuscular implants. Persistent/Recurrent Hyperparathyroidism in MEN 1 Patients Permanent hypoparathyroidism occurs in less than 10% of, patients undergoing subtotal parathyroidectomy, and most series describe rates in the range of 1% to 2%.529 The rates of permanent hypoparathyroidism range from 10% to 30% undergoing total parathyroidectomy with imme- diate autografting 5% Total parathyroidectomy, however, has been associated with recurrence rates as low as 0 (range, 0 to 60%), whereas recurrence rates for subtotal parathy- roidectomy have never been reported less than 4% (range, 4% to 20%).#5519" Persistent HPT is generally less than 5% with both procedures.” Malmaeus and coworkers found that when 1 to 2.5 glands were removed, persistent HPT occurred in 24% and recurrent disease in 62%. The recurrence and persistence rate was 0 in 18 patients under- ‘going total parathyroidectomy (Table 76-4). 2 Persistent HPT occurs because of misdiagnosis of hyper- plasia and incomplete resection. Recurrent HPT is generally678 —— Endocrine Pancreas eee hOniet teen aub ee jecurren Persistent Permanent Permanent Operative Procedure ice HPT(%) __Hypoparathyroidism (%) Laryngeal ro J ‘Subtotal parathyroidectom 420 <6 <10 (mmost 1-2) <1 Total parathyrodecromy 0.60 Formal Techour fasts for insulinoma and provocative testing for sastrin are applied selectively. a ANTERIOR ae 76-8, Somatostatin receptor scintigraphy (left [anterior] and right [pos ‘tum with muliple hepatic metastases. Muluple Endocrine Neoplasia Type 1 —— 683 5 FIGURE 76-7. Endoscopic ultrasonography of a hypoechoic islet cell tumor in the pancreatic body (arrow). Imaging Conventional imaging (percutaneous ultrasound, CT, MRI) modalities for the carly detection of pancreatic duodenal endocrine tumors is fraught with hazard; both low sensitivi- ties and specificities have rendered the earlier mentioned biochemical screening protocol even more important. «74+ The sensitivity for endoscopic ultrasonography, however, may be as high as 90% (Fig. 76-7)."'5! Diagnostic accuracy increases when somatostatin receptor scintigraphy (Fig. 76-8) correlates with endoscopic ultrasonographic findings.'*™'5! Endoscopic ultrasonography also offers the opportunity for directed fine-needle aspiration cytology. We discourage this for tumors in the pancreatic head because efforts at enucleation may be thwarted by even the slightest amount of bleeding and inflammation. If this does occur, surgery should be delayed for several weeks to allow resolution to take place. The efficacy of PET scanning for pancreatic duodenal endocrine tumors remains to be determined.'* Who Should Undergo Surgery? Patients with two rising independent serum markers, regard less of negative imaging, should be explored (Table 76-8)."? PosTrRioR jor)) demonstrating a gastrinoma in the region of thesli 684 — Endocrine Pancreas TABLE 76-8. Indications for Pancreatic/ nese noe u ‘Two rising (independent) biochemical markerst ‘An elovated biochemical marker plus an unequivocal imaging study? ‘Two concordant unequivocal imaging studies in the absence of elevated biochemical markers! dey ae ca a exctaly ea Bb SOA OG =a TERE prsoaaia ead iinpenmats poppe tarccg ee en Sv y ‘maging study: EUS + fine-needle aspiration. Se shes das in eee nae Ma ‘multiple endocrine neoplasia type 1: EUS = endoscopio Moalited' fom fom Shogeeld 3, Rastad J, Akarstom 0. Pancreatic tndocrine tumors mn mutipis endosiae mason ores Donerty Gut Stogoo p(s}, Suga Endootrology Pein, placa Was Wala Soo An elevated biochemical marker and an unequivocal imaging study (endoscopic ultrasonography plus fine-needle aspiration) or concordant endoscopic ultrasonography and somatostatin receptor scintigraphy in the absence of biochemical markers would be the other indications, in the absence of distant metastatic disease.!? In carriers of germline mutations who have a single positive biochemical marker, imaging should be carried out yearly (but every 3. years for those with negative biochemistry)."? Some centers now rely exclusively on endoscopic ultrasonography for screening, but further validation is warranted. Hypoglycemic Syndrome Insulinoma associated with endogenous _hyperin- sulinism is the most common functioning PET in MEN 1 ents younger than 25 years of age."? Although these patients often have multiple pancreatic tumors, typically only one is the source of insulin excess."? This raises the question of whether selective arterial calcium stimulation testing with hepatic vein sampling for insulin should be considered.'®”4°5 Although insulinomas are most often benign, there is no effective medieal therapy. Without surgery, hormonal sequelae remain debilitating and life- threatening. Surgery involves an 80% distal pancreatectomy to the right of the superior mesenteric vein with enucleation (Fig. 76-9) of any remaining pancreatic head tumors, using IOUS." ‘This removes the insulinoma(s) as well as many of the non- functioning tumors capable of malignant transformation. Splenic preservation may be possible in young, thin patients by carefully separating the splenic vein from the underside of the gland using fine metal clips and an ultrasonic dis- sector. Small spleens can be preserved on the short gastric vessels alone, Recurrence rates in patients with MEN 1 are higher than in sporadic cases but nonetheless are acceptable. Leaving behind 20% of the pancreas generally limits recurrences and avoids endocrine insufficiency in most cases. FIGURE 76-8. Enuclestion ofan islet cell tumor in the pan head, Dissection of the pancreas “away from tumor” wages endarterectomy spatula and minimal bipolar cautery is iar’, Grom Thompson GB. Islet cell tumors. In: Mayo Cae’ Gastrointestinal Surgery. Philadelphia, WB Saunders, 20035 Other Pancreatic Endocrine Tumors MEN I patients with malignant islet cell tumors (glucagono. mas, VIP tumors, PTHrp tuinors, and some insulinoma deserve an equally, if not more aggressive approach, includ. ing an 80% distal pancreatectomy, splenectomy, and lymphadenectomy, along with enucleation of any residual tumors. Isolated liver metastases or a finite number of mul- Uiple hepatic metastases can be successfully managed, with excellent control of hormonal sequelae, using a combination of hepatic resection and radiofrequency thermal ablation, 518 Zollinger-Ellison Syndrome Gastrinomas represent the most common functioning pancreatic/duodenal endocrine tumors in MEN I patients.!"" Nearly one third of ZES patients are MEN I kindred members, and more than 50% of MEN 1 patients have hypergastrinemia, Jn the past, surgery for MEN 1 ZES was carried out with reluctance, if at all.'5*"® Cure rates were low, based on nor- malization of gastrin levels, and medical therapy in the form of proton pump inhibitors (PPIs) has been extremely effec- tive at eliminating peptic acid sequelae. Medical therapy does not, however, prevent malignant transformation, not does it prevent the development of metastatic disease.” Presently, 30% to 50% of patients undergoing surgical exploration have at least regional nodal metastases, many o! which are amenable to resection, often providing excellent Palliation. 5! More than 80% of gastrinomas in MEN | Patients are duodenal in origin.3°.157 In addition. ZES Patients appear at greater risk for malignant transformation of nonfunctioning tumors when compared to other MEN ! Patients.''®® Norton and colleagues have shown that patients with nodal metastases can achieve similar survival benefits with operative intervention compared to those with out lymph node involvement. '®! Gastrin levels often rise ate in MEN I patients. Once the gastrin level is elevated. 30% to 50% of patients already harbor nodal metastases even it the face of negative imaging studies. Resection of large? (3-cm) PETs does not appear to reduce the risk of develo? ing liver metastases, once again making a strong argument fo" screening, early detection, and early surgical intervention:‘he ‘most often performed has been popularized yy De Norman Thompson atthe University of Michigan at Me Atbor (Fig. 76-10).'29718168 The surgery is carried A er adequate treatment with PPIs to heal active ulcers. fanibioics and deep venous thrombosis prophylaxis are prided. The abdomen is thoroughly explored through miverse epigastric or chevron incision, Careful attention i paid to the liver, which is explored both by palpation and {OUS. The gastrocolic omentum is completely mobilized fffthe transverse colon from left to right, entering the lesser Sox Both colonic flexures are mobilized and retracted cau- {ally. The duodenum is widely kocherized out to the liga- tren of Treitz, The avascular plane along the inferior border ifthe pancreas is incised and the pancreatic body is freed to {s superior border. The lienorenal and iienophrenic liga- iments are divided using electrocautery, and the spleen, body, ind til of the pancreas are mobilized to the splenic vein- siperor mesenteric vein junction. The inferior mesenteric tein may require division to further facilitate exposure. The Superior mesenteric vein is then isolated from the neck of the pancreas. Division of the anteroinferior pancreaticoduo- denal vein, as well as the right gastroepiploic vessels, aug- renis exposure of the uncinate and pancreatic head and reduces the risk of avulsing these delicate veins as the oper- ation proceeds. At this point, careful bidigital palpation of theentire gland is carried out along with IOUS in anteropos- teior planes and transverse-longitudinal directions. S| attention is paid to the location of the pancreatic and ducts and their relationship to nearby islet cell tumors. Lymph nodes are removed from along the posterior aspect of the pancreatic head, the kepatoduodenal ligament, the subpy- lore region, branches of the celiac artesy, and the proximal supetior mesenteric artery. In patients with hypergastrinemia, 2 longitudinal duodenctomy is made along the free wall of the second portion of the duodenum. The duodenal wall is, POURE 76-10, Eighty percent distal pancreatectomy (splenic Ring), enuclestions i 4 (pancreatic head), exploratory duodeno: pe lymphadenectomy for a patient with multiple endocrine (Coxeny (MEN) type 1 and Zollinger-Ellison syndrome. ‘toy, 4f.of Dr. Norman Thompson, University of Michigan, Ann Michigan.) Multiple Endocrine Neoplasia Type 1 —— 685 carefully palpated between thumb and index finger proxi- mally across the pylorus and distally beyond the ligament of Treitz. The duodenal mucosa is intussuscepted into the duo- ‘Duodenal carcinoids are the principle cause of ZES in MEN 1 patients" They are often multiple and frequently metastasize to regional lymph nodes and subsequent to the liver, Gastric carcinoids can be gastrin producing (highly malignant) or can evolve secondary tothe hypergastrinemia from gastrin;producing duodenal carcinoids (enterochro- ‘maffin cell hyperplasia).2!"% Treatment requires excision and lymphadenectomy and, less often, gastrectomy or pancreatoduodenectomy, depending on the extent of foregut involvement. herited tumo disorder caused by mutations in the MEN/ t ae jumor suppressor e = (craosome 13) Theiagoose is made in peas by cucu ‘of the three major manifestations Cetin HPT [>954], pancreatic neuroendocrine ie ae 75%}, or pituitary tumors (30% to 55%) a rating one major manifestation in an at-risk ly member of a known MEN 1 kindred. Genetic testing ion is clearly indicate rseion lt agonoas, VIP irs, ad Prcioning tumors. There is increasine evidence suggesting fanetrly surgical intervention for MEN W/ZES patients and patients with subclinical pancreatic neuroendocrine tumors ate ult in prolonged palliation and a redvctich © the rate does gant transformatcn. Since biochemical abnormalities oral ected decades prior othe development of over lin. carve Tapioms, genetic testing, biochemical sereening, and Jnaging of appropriately selected patients appear ‘warranted. Acknowledgments “The authors thank Abbie L. Young, critique ofthis chapter MS, and Dr. Britt Skogseid for their REFERENCES 1 Erdem J Zar normalen und pthologchenNistlogie der sana ern you papi Bes Fo! OE 2. 6 utermalgetmoven der dasen it ine skein be » fermen nk ao 38233 . Wermer® Gena spss of aenonatosiof endocrine Med 1954;16:363. 7 ren ee 4, son. StoscidB, Oberg Kt Mul endosine 2 type I gene maps to. ‘chromosome I and is “ in ain tre opel 11 ands ot in instinoma Nate 3 Ther RBs. Wosdg Ct a Awaxsion pai rms alipe exer neplaca ype | wih tof les comune HEN ol Met 9991 218 Brame Laon 6 Bm Ctl Latin fe ee mt ci apn sa gon win ee teh yon apg tr, Ps Nas as U 8A 1. Pda ie hens Bs Sekaguchi iN Bale AE, et al, Clonality of parathyroid Se W Eat Med teens Lis IN, Yen HF, Lan CHW, mute ns nt 5 gran i Re cena oP Send ML Male ic pnp Gn eae aim nl ea 1 ice Me Nah oc Cb rae A aia ipl | memset oles Yr an Lt Ht. Cra ma ice nob AEN stepected patients: MEN I axe finding, Bur} CH