Surg Today (2008) 38:1137–1143 DOI 10.1007/s00595-008-3763-1

Cervical Metastases of in a Patient with Multiple Endocrine Neoplasia Type 1: Report of a Case

1 2 3 3 4 2 JEAN M. BUTTE , PABLO H. MONTERO , ANTONIETA SOLAR , JAVIERA TORRES , PABLO R. OLMOS , IGNACIO GOÑI , 5 1 1 JUAN C. QUINTANA , JORGE MARTÍNEZ , and OSVALDO LLANOS

Departments of 1 Digestive Surgery, 3 Pathology, 4 Nutrition and , and 5 Radiology, and 2 Section of Surgical , Faculty of Medicine, Pontifi cia Universidad Católica de Chile, Marcoleta 367, Santiago, Chile

Abstract Key words Multiple endocrine neoplasia type 1 · Glu- Multiple endocrine neoplasia type 1 (MEN 1) is a syn- cagonoma · Cervical metastases · Surgical treatment drome characterized by tumors of the parathyroid , pancreatic islet cells, duodenum, and pituitary . We report a case of cervical metastases of gluca- gonoma with MEN 1. The patient was a 34-year-old Introduction woman admitted to our hospital with epigastric pain. Her medical history included two resections of prolac- Multiple endocrine neoplasia type 1 (MEN 1) is an tinoma and two upper GI hemorrhages secondary to uncommon syndrome, which was fi rst described in 1954 duodenal ulcers. Computed tomography (CT) showed by Werner. It is characterized by hyperparathyroidism two hypervascular lesions in the tail of the and (>90%), endocrine tumors of the pancreas and duode- cervical ultrasound showed multiple hypoechogenic num (65%–75%), and tumors of the anterior hypophy- ovoid images in the neck. A cervical CT scan confi rmed sis (30%–65%).1 Any of these lesions may be the fi rst two 15-mm lymph nodes in the left cervical region to appear.2 The low incidence and great variability in its and 111In-DOTATOC imaging showed focal abnormal clinical presentation, coupled with nonspecifi c symp- expression in the pancreatic tail and the toms plus an unpredictable disease course, generally cervical nodes. The patient had asymptomatic hypogly- delay the diagnosis and treatment.1 The clinical mani- cemic episodes, with blood sugar levels as low as 30 mg/ festations that suggest this disease include hyperpara- dl, which raised our suspicion of MEN 1 associated with thyroidism before the age of 50 years, multiglandular or pancreatic . Thus, we performed a distal pan- recurrent hyperparathyroidism in patients without renal createctomy with bilateral cervical dissection and para- disease, any lesion of MEN 1 in a relative of a MEN 1 gland resection. Histopathological examination carrier, any lesion of MEN 1 associated with suprarenal revealed 12 pancreatic tumors as well as metastases involvement, endocrine tumors of the pancreas and in four cervical lymph nodes. The resected parathyroid duodenum, and thymus or bronchial .2 glands had normal structure, suggesting parathyroid The prognosis of these patients depends on the tumor . A follow-up CT scan, 18 months after type and whether there are metastases, which generally surgery, showed new tumors in the head of the pancreas involve the regional lymph nodes or liver. Cervical and in the duodenal wall. A pancreatoduodenectomy lymph node metastases are exceedingly rare and the was performed and histopathological examination treatment and prognosis of these patients are not well revealed nine nonfunctioning endocrine tumors in the defi ned.3 pancreas, one tumor in the duodenal wall, and metasta- We report an unusual case of cervical lymph node ses in two peripancreatic lymph nodes. The patient metastases of a primary glucagonoma of the pancreas recovered well and remains asymptomatic. in a patient with MEN 1. To the best of our knowledge, this is the fi rst report of cervical lymph node metastases of glucagonoma.

Reprint requests to: J.M. Butte Received: September 11, 2007 / Accepted: January 9, 2008 1138 J.M. Butte et al.: Cervical Metastases of Glucagonoma with MEN 1

Case Report pancreatic tail (Fig. 1B) and in the cervical lymph nodes (Fig. 1D). A 34-year-old woman was admitted to our hospital with During her hospital stay, the patient suffered two a 10-day history of colicky pain in the epigastric and episodes of spontaneous asymptomatic right upper quadrant regions, vomiting and with blood sugar levels as low as 30 mg/dl, which were fi ve to six times a day, and a 3-kg weight loss in the last treated with intravenous 30% solution. This month. Her medical history included two raised our suspicion of MEN 1 associated with a pan- resections, 9 and 8 years earlier, respectively; secondary creatic insulinoma. The results of a fasting test were ; and primary hypothyroidism. She had also compatible with insulinoma. The laboratory data, in suffered two episodes of gastrointestinal hemorrhage the presence of blood glucose below 40 mg/dl were as secondary to a single duodenal ulcer 3 years earlier. The follows: insulinemia, 30.5 uUI/ml (normal range 6– patient had no familial history of . 27 uUI/ml); C-, 5.4 ng/dl (normal range 0.5–4 ng/ Physical examination revealed a 3 × 3-cm hard, non- dl); calcium, 10.5 mg/dl (normal range 8.5–10.5 mg/dl); mobile, nontender in the left cervical region. gastrin, 270 pg/ml (normal range <200 pg/ml); intraplate- Multiple skin lesions of fatty consistency were seen over let serotonin, 353 ng/109 platelets (normal range 400– her abdomen, but they were regarded as nonspecifi c 800 ng/109 platelets); basal <0.5 pg/ml (normal and did not resemble necrolytic migratory erythema. range >13 pg/ml); and intact parathyroid , She had right upper quadrant tenderness with no pal- 177 pg/ml (normal range 11–67 pg/ml). The serum levels pable masses or Murphy’s sign. of were not measured at the time. 99mTc-MIBI Abdominal ultrasound and magnetic cholangioreso- showed signs of glandu- nance showed gallstones with a normal extrahepatic lar hyperplasia (Fig. 1D). biliary tract. An abdominal computed tomography An open biopsy of the cervical lymph nodes revealed (CT) scan showed two hypervascular tumoral lesions a dense, infi ltrating epithelial tumor with positive in the pancreatic tail and infl ammatory changes in immunohistochemical staining for glucagon, chromo- the periduodenal zone (Fig. 1A). Upper gastrointesti- granin-A, synaptophysin, and enolase, and negative nal endoscopy showed duodenitis and a cervical ultra- immunohistochemical staining for and neurofi la- sound demonstrated multiple hypoechogenic ovoid ment (Fig. 2). These fi ndings were compatible with cer- images in the left cervical region compatible with vical lymph node metastases of an endocrine , enlarged lymph nodes, up to 2.7 cm in diameter. We and suggested a combination of glucagonoma and performed 111In-DOTATOC (111In-tetraazacyclododec- insulinoma. ane-tetraacetic acid-Tyr3-) imaging, which We performed distal , splenectomy, showed somatostatin receptor overexpression in the and cholecystectomy (Table 1). The intraoperative

AB Fig. 1A,B. 111In-tetraazacyclododecane- tetraacetic acid-Tyr3-octreotide (111In DOTATOC) SPECT/computed tomog- raphy (CT) image fusion. A Transverse CT image of the abdomen. B Transverse SPECT/CT fusion image. There is a focal area of abnormal somatostatin expression located in the tail of the pancreas corre- sponding with the tumor visible on the CT image (white arrow). C,D 99mTc MIBI SPECT/CT image fusion. C Coronal CT CD image of the neck. D Coronal SPECT/CT fusion image. There are three areas of abnormal uptake: the intense right para- sagittal focal area, corresponding to an enlarged right superior parathyroid gland; the inferior left parasagittal area, corre- sponding to an enlarged ectopic parathy- roid gland; and a faint area in the left lateral cervical area, corresponding to enlarged lymph nodes (metastatic gluca- gonoma) located medial to the sterno- cleidomastoid muscle (black arrow) J.M. Butte et al.: Cervical Metastases of Glucagonoma with MEN 1 1139

ADB

E F

Fig. 2. A–D First resection of lymphatic cervical metastases (×400). E–H Cervical dissection of lymphatic metastases. of neuroendocrine carcinoma (glucagonoma). A Lymph node E Lymph node metastases. Positive immunohistochemical metastases (H&E, ×40). B Medium-sized cells with uniform stain for glucagon (×40). F Medium-sized cells with uniform and bland nuclei arranged in solid nests (H&E, ×400). and bland nuclei arranged in solid nests (H&E, ×400). C Focally positive immunohistochemical stain for glucagon G Positive immunohistochemical stain for glucagon (×400). (×400). D Negative immunohistochemical stain for insulin H Negative immunohistochemical stain for insulin (×400)

Table 1. Sequence of surgery and histopathological fi ndings Sequence Surgical procedure Histopathological study

Initial presentation Distal pancreatectomy, splenectomy and Twelve pancreatic tumors. cholecystectomy Immunohistochemical study was positive for insulin, glucagon, somatostatin and vasoactive intestinal peptide. Twelve peripancreatic lymph nodes were negative for neoplasia 1 month later Bilateral cervical dissection and parathyroid Metastases in 4 of 22 resected lymph nodes, all gland resection with implantation of one of of which were metastases of glucagonoma. these into her forearm The parathyroid glands had normal structure and parathyroid hyperplasia 18 months later Pancreatoduodenectomy Nine pancreatic and one duodenal tumor. Immunohistochemical study was positive for insulin, glucagon, somatostatin and vasoactive intestinal peptide. Two peripancreatic lymph nodes were positive for metastases of glucagonoma

ultrasound showed at least three other lesions in the were also scattered, and ranged in size from 1 to 3 mm. body of the pancreas, but as no other lesions were All these tumors were confi ned to the pancreas and did detected in the liver, or elsewhere in the abdomen, we not infi ltrate the peripancreatic adipose tissue. The sur- performed partial instead of total pancreatectomy. The gical borders were free of tumor and no vascular per- gallbladder had infl ammatory changes with an impacted meation or perineural infi ltration was found. Twelve stone in its neck. The postoperative course was unevent- peripancreatic lymph nodes were studied, and all were ful and the insulinemia decreased to 8.5 uUI/ml, with negative for neoplasia. Immunohistochemical analysis consistently normal serum glucose levels for 10 days. revealed intense positivity for insulin in the 1.8 × 1 × Histopathological examination of the distal pancreas 1.2-cm tumor, but scarce and focal positivity for insulin revealed 12 pancreatic tumors, 6 of which were macro- in the remaining ones. Most of these other tumors were scopic and 6, microscopic. The largest tumor, located in positive for glucagon, somatostatin, and vasoactive the tail of the pancreas, was 1.5 × 1.5 × 1 cm. The other intestinal peptide (VIP; Fig. 3). The adjacent pancreatic macroscopic tumors, spread throughout the pancreatic tissue showed signs of chronic pancreatitis and nesidio- tissue, ranged from 3 to 13 mm. Microscopic tumors blastosis-like changes. These fi ndings were compatible 1140 J.M. Butte et al.: Cervical Metastases of Glucagonoma with MEN 1

Fig. 3. A Resected pancreatic body and tail. Sectioned in the trabecular (B) and the other had a solid growth pattern (C). major axis, seven tumors can be seen (black empty circles). Both contained medium-sized cells with basophilic cytoplasm Two tumors in the tail (black oval), one above the other, are and uniform, round, small nuclei of granular chromatin (H&E, round and well delineated. The superior nodule is grayish- ×400). D Insulinoma histology showing tumoral cell cords in white and fi rm, and the inferior one is soft, reddish black, and an abundant and hyaline stroma (H&E, ×400). E Positive hemorrhagic, corresponding with the insulinoma. The others immunohistochemical stain for Vipoma (×400). F Positive are pinkish-white and well delineated, and some are cystic. immunohistochemical stain for glucagonoma (×400). G Posi- B,C Histology of two of the tumors from the body of the tive immunohistochemical stain for somatostinoma (×400). pancreas. They showed different growth patterns: one was H Positive immunohistochemical stain for insulinoma (×400)

with a diagnosis of MEN with insulinoma and gested endocrine tumors of the remaining pancreas and glucagonoma. duodenum. We regarded these as potential sources for A follow-up cervical CT scan performed 1 month new metastases, so the patient was admitted for a third postoperatively showed at least two 15-mm lymph nodes time, to undergo pancreatoduodenectomy, which was in the left cervical region and a 10 × 16-mm hypervas- performed about 18 months after her initial admission. cular nodule in the right inferior thyroid lobule, which Although serum samples were obtained just before pan- were suggestive of parathyroid (Fig. 1C). The creatoduodenectomy, the serum levels of glucagon were patient did not have any symptoms of hyperparathy- not known at the time of writing as the samples were roidism and her serum calcium levels were normal. She sent to another country for analysis. was readmitted and underwent bilateral cervical dissec- Histopathological examination at this point revealed tion plus parathyroid gland resection, followed by the nine pancreatic and one duodenal tumor (Fig. 4). All implantation of one of these glands into her forearm. the pancreatic tumors were microscopic, and ranged Histopathological examination revealed metastases in from 1 to 4 mm. The duodenal tumor measured 6 × 5 × 4 of 22 resected cervical lymph nodes, all from the 4 mm. The pancreatic tumors were confi ned to the pan- left side. The largest was 2.2 cm. All were creas and did not infi ltrate the peripancreatic adipose reported as lymph node metastases of glucagonoma. tissue. The surgical borders were free of tumor and no The parathyroid glands had normal structure; the right vascular permeation or perineural infi ltration was found. superior one weighing 276 mg, the right inferior, 89 mg, Two peripancreatic lymph nodes were positive for the left superior, 74 mg, and the left inferior, 168 mg, tumor cells, which proved to be metastases of gluca- suggesting parathyroid hyperplasia. The metastases did gonoma. Immunohistochemical analysis of the pancre- not involve perinodal tissue and their histological atic tumors revealed positivity for insulin, glucagon, appearance was similar to that of the previous cervical somatostatin, and VIP, similar to the tumors from the biopsies (Fig. 2). fi rst pancreatic resection 18 months earlier. The adja- After the neck surgery, the patient remained asymp- cent peripancreatic tissue showed signs of nesidioblastosis- tomatic for 6 months, until the development of diabetes like change. A tumor was found in the duodenal mellitus requiring insulin. Follow-up CT images 18 submucosa, which consisted of uniform, small to medium months after the fi rst pancreatic surgery procedure sug- tumoral cells with round to oval regular nuclei, having J.M. Butte et al.: Cervical Metastases of Glucagonoma with MEN 1 1141

Fig. 4A–C. Macroscopic view of the pan- creatoduodenectomy. There were multi- ple tumors in the head of the pancreas and one tumor in the duodenal wall (black circle and black arrow in A and C)

similar characteristics to the other tumors in the pan- of insulinoma was based on hypoglycemic episodes and creas. Immunohistochemical analysis revealed positiv- the unsuppressed plasma level of insulin and C-peptide ity to calcitonin and negativity to insulin, glucagon, during the fasting test, whereas the diagnosis of gluca- somatostatin, gastrin, and VIP. Since her last operation gonoma was based on histological and immunohisto- the patient has been asymptomatic, and her diabetes is chemical fi ndings. The diabetes mellitus in our patient being controlled well with intensive insulin therapy. can be explained by the presence of a glucagonoma fol- lowed by partial and then total pancreatectomy; however, it has been reported that diabetes and impaired fasting Discussion glucose occurs more frequently in MEN 1 patients.5 Somatostatin analog imaging with 111In-DOTATOC Multiple endocrine neoplasia type 1 is an autosomal- also proved helpful for the diagnosis of an endocrine dominant syndrome characterized by a mutation in the tumor and its metastases, although this procedure is not MEN 1 located in the long arm specifi c for a particular endocrine tumor.2 of chromosome 11. The clinical expression of this disease Bartsch et al.1 recently reported that 77% of a series varies, although the most frequent presentation includes of MEN 1 patients presented with multiple tumors in primary hyperparathyroidism, endocrine tumors of the the duodenum or pancreas, or both. They noted that pancreas and duodenum, and tumors of the anterior was the most frequent tumor and that 38% hypophysis. Occasionally, tumors and of the patients presented with a malignant tumor, with thymus, bronchial, or gastric endocrine neoplasia are involvement of regional lymph nodes and distant metas- observed. A diagnosis of MEN 1 requires involvement tases. In another series of 508 patients with MEN 1 of at least two of the most frequently affected organs; reported by Lévy-Bohbot et al.,6 58% presented with namely, the hypophysis, parathyroids, duodenum, and duodenal or pancreatic tumors, or both, which were pancreas.2,4 We did not screen the relatives of our patient multiple in 26.4%. Gastrinoma was the most frequent as she is childless and the single daughter of elderly tumor, then insulinoma. It is noteworthy that in that parents. series, only 1.6% of the patients presented with gluca- The association of a resected pituitary prolactinoma gonoma, another 0.98% had VIPoma, and just 0.56% with other multiple endocrine pancreatic tumors in our had somatostinoma. The patients with VIPoma or patient was highly suggestive of MEN 1. The diagnosis somatostinoma had a higher incidence of metastases 1142 J.M. Butte et al.: Cervical Metastases of Glucagonoma with MEN 1 than those with an insulinoma or a gastrinoma. In this pancreatectomy has not been shown to improve sur- context, the MEN 1 in our patient should be regarded vival, we did not perform pancreatectomy at this stage. as belonging to the 38% that are malignant, to the When neck nodes became apparent, we performed 26.4% that are multiple, and to the 1.6% that are cervical dissection considering the better survival of glucagonoma. patients with metastasic glucagonoma submitted to R0 It was reported that pancreatic tumors and their resection and the low morbidity of surgery. Close follow- metastases are the main cause of death of MEN 1 up with imaging showed the lesions in the head of the patients.7 The association of multiple pancreatic tumors pancreas and duodenal wall 18 months after the initial from different cellular precursors and cervical gluca- pancreatic surgery. When we performed the second gonoma metastases is a rare manifestation of this disease operation on the pancreas, we did not fi nd concomi- and could be the main prognostic factor for the long- tant metastases, so we restricted the procedure to a term survival of our patient. However, it is precisely the . lack of previously reported cervical lymph node metas- After the second pancreatic operation, histopatho- tases of glucagonoma that makes it diffi cult to predict logical examination revealed several endocrine tumors our patient’s prognosis. To illustrate this point, Soha and in the head of the pancreas and one tumor in the duo- Yakuwa,3 in their exhaustive meta-analysis of 407 cases denal wall. These lesions all had the same histology and of glucagonoma, reported 10-year survival in 64.3% of immunohistochemical features as the tumors resected the whole cohort, and in 51.6% of 209 (51.4%) patients from the body and tail of the pancreas 18 months before. who had metastases involving the liver (79.9%), local The lesions in the head of the pancreas were small and lymph nodes (37.8%), bone (8.1%), mesenterium well differentiated, but the presence of two positive (4.8%), lung (2.9%), or adrenal gland (1.4%); however, lymph nodes made the prognosis of the patient less none of these patients had distant lymph node metasta- certain. Similar immunohistochemical features of lymph ses. The reader could argue that these data were appli- node metastases were described by Kawakita et al.13 cable only to in general, but not to those Despite this and the chance of new tumors, we believe in patients with MEN 1. To explore this possibility, we that close follow-up to detect lesions early, followed by focused on reported cases of glucagonoma in the context radical resection might improve the prognosis of such of MEN 1. We found three publications describing a col- patients.11,12,14 lective seven patients with glucagonoma + MEN 1, none Most neuroendocrine tumors exhibit neuroamine of whom had distant (neck) lymph node metastases.6,8,9 uptake mechanisms or specifi c receptors, such as soma- Approximately 80% of patients with an isolated glu- tostatin receptors (SSTRs), in the cell membrane. These cagonoma have visceral metastases at the time of diag- receptors can be used for identifi cation, localization, nosis, compared with 40% of those with glucagonoma and therapy. By using locally available radiopharma- associated with MEN 1.6 This is higher than that of ceuticals such as 90Y-DOTATOC or 177Lu-DOTATATE, patients with an isolated gastrinoma or insulinoma. it is now possible to deliver a radiation dose specifi cally Despite the high rate of metastases in patients with targeted to a somatostatin receptor overexpressing a glucagonoma + MEN 1, survival rates of 100%, 53.8%, , sparing the surrounding normal and 53.8% at 5, 10, and 20 years, respectively, were tissue. Reported objective tumor size responses of reported.6,7 Sarmiento et al.10 operated on 23 patients 25%–30% have been obtained using these agents. with synchronous liver metastases of pancreatic endo- Patients who benefi t from this type of treatment are crine tumors, which were secondary to glucagonoma in those with inoperable or metastatic neuroendocrine 6. The tumor was completely resected in 9 (26%) tumors such as gastro-entero-pancreatic tumors, a high patients and the 5-year survival of all treated patients level of somatostatin receptor expression demonstrated was 71%, the main cause of death being local tumor by 111In-labeled somatostatin analog imaging, good progression. Norton et al.11 operated on 18 patients with renal (glomerular fi ltration rate >40 ml/min) and bone liver metastases of nonpancreatic endocrine tumors, marrow reserve (hemoglobin >10 g/l, white blood cells and reported a 5-year survival rate of 82%. Radny >3.0 × 109/l, platelets >100 × 109/l), and good perfor- et al.12 performed liver transplantation as aggressive mance status. It has been suggested that early treat- treatment for metastatic glucagonoma in one patient, ment, particularly for patients with progressive disease, who survived for up to 72 months. may achieve better outcome.15–19 Although our patient We believe that total pancreatic resection was justi- fulfi lled these criteria for the therapeutic use of soma- fi ed for our patient, not only for symptomatic relief, but tostatin analog, we did not give her this treatment oncologically. At the time of her initial distal pancre- because it was expensive and not covered by her insur- atectomy, the absence of disease in the pancreatic head, ance. Moreover, we did not perform selective arterial the levels of gastrin, and her clinical presentation did secretin or calcium injection tests to search for a gastri- not suggest a gastrinoma and because prophylactic total noma because the patient did not have a classical hyper- J.M. Butte et al.: Cervical Metastases of Glucagonoma with MEN 1 1143 gastrinemic syndrome and her basal gastrin levels were tumors in 28 patients with multiple endocrine neoplasia, type I. all normal. Am J Pathol 1996;20:1378–84. + 10. Sarmiento J, Que F, Grant C, Thompson G, Farnell M, Nagorney In summary, we reported a case of glucagonoma D. Concurrent resections of pancreatic islet cell with syn- MEN 1 with unusual distant metastases in the lymph chronous hepatic metastases: Outcomes of an aggressive approach. nodes of the neck. The long-term survival of this patient Surgery 2002;132:976–83. was probably favored by the careful search for, and 11. Norton J, Warren R, Kelly M, Zuraek M, Jensen R. Aggressive surgery for metastatic liver neuroendocrine tumors. Surgery surgical removal of, the offending tissue. 2003;134:1057–65. 12. Radny P, Eigentler T, Soennichsen K, Overkamp D, Raab H, Viebahn R, et al. Metastatic glucagonoma: Treatment with liver References transplantation. 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