Surg Today (2008) 38:1137–1143 DOI 10.1007/s00595-008-3763-1 Cervical Metastases of Glucagonoma 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 Diabetes, and 5 Radiology, and 2 Section of Surgical Oncology, 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 glands, pancreatic islet cells, duodenum, and pituitary gland. 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 pancreas 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- somatostatin 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 insulinoma. 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 thyroid 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 carcinoid.2 glands had normal structure, suggesting parathyroid The prognosis of these patients depends on the tumor hyperplasia. 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 hypoglycemia right upper quadrant regions, vomiting and diarrhea 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% glucose solution. This month. Her medical history included two prolactinoma 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 amenorrhea; 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 cancer. 27 uUI/ml); C-peptide, 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 nodule 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 calcitonin <0.5 pg/ml (normal and did not resemble necrolytic migratory erythema. range >13 pg/ml); and intact parathyroid hormone, 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 glucagon were not measured at the time. 99mTc-MIBI Abdominal ultrasound and magnetic cholangioreso- parathyroid gland scintigraphy 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 insulin 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 carcinoma, 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-octreotide) imaging, which We performed distal pancreatectomy, 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.