Spinal metastasis as the initial manifestation of a nonsecretory glucagonoma. (Case Report).

Abstract

Glucagonomas are rare functional endocrine tumors of the pancreas that classically present with symptoms of glucagon excess, including rash, hyperglycemia, diarrhea, and weight loss. Metastatic disease at presentation is common but is often limited to the liver and regional lymph nodes. We describe an unusual case of a patient with glucagonoma who presented with a pathologic vertebral fracture. This tumor had no evidence of active hormone secretion but tested positive for glucagon by immunohistochemical staining.

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Glucagonomas are neuroendocrine tumors that arise from [alpha] cells of the pancreatic islets. These tumors are often associated with a clinical syndrome caused by the metabolic effects of glucagon. The glucagonoma syndrome includes increased hepatic gluconeogenesis and hyperglycemia, muscle catabolism with associated wasting, and an unusual cutaneous eruption known as necrolytic migratory erythema, sometimes with associated stomatitis or cheilosis. (1-3) Diarrhea and gastrointestinal complaints are common, especially when the tumor secretes other peptide hormones in addition to glucagon, such as vasoactive intestinal peptide or gastrin. (2) Venous thromboembolisin is unusually common in patients with this malignancy. (2,4) Glucagonomas are rarely benign and often metastasize to the liver and the lymph nodes (2,5) but can also metastasize to distant organs, including bone, in the later stages of the disease. (2,6,7) We describe a case of a glucagonoma metastatic to bone at presentation. The patient had no evidence of systemic glucagon excess, so the diagnosis was made on the basis of positive immunohistochemical staining of the tumor for glucagon. This case illustrates that glucagonomas can metastasize widely and that they are not always associated with clinical evidence of glucagon excess.

Discussion

To our knowledge, there has been only one other report of bone metastases as the initial clinical manifestation of glucagonoma. (7) Our case also illustrates that the absence of hormonal derangements does not exclude the possibility of a glucagonoma. Although endocrine manifestations of glucagonomas are common in advanced disease and may be related directly to tumor size, (2,8,9) the absence of clinically important secretory activity can be observed even in patients with widely metastatic disease. Notably absent in our patient were mucocutaneous lesions, gastrointestinal complaints, and hyperglycemia. There was also no evidence of excess tissue catabolism, such as weight loss or hypoalbuminemia, which can be induced by high levels of glucagon or by metastatic cancer alone. (3,10) Because many glucagonomas come to clinical attention through the effects of high serum levels of glucagon, (9,11,12) we speculate that the lack of clinically important secretory activity of our patient's tumor allowed it to evade dia gnosis until it caused a spinal compression fracture. There is no clear evidence, however, that nonsecretory glucagonomas generally carry a worse prognosis or present later than do those that are hormonally active.

Another important clinical feature in our patient was the absence of a definite pancreatic mass, despite extensive adenopathy and widespread metastases. Although initial pathologic analysis showed that the tumor was composed of neuroendocrine cells, there was still uncertainty regarding the site of origin. Small cell carcinoma of the lung, carcinoid tumors of the gastrointestinal tract, and islet cell tumors of the pancreas all can present as neuroendocrine tumors of unknown primary. Because the prognosis and treatment of patients with neuroendocrine malignancies depend on knowing the tumor type, (13-16) we performed endoscopic and radiographic evaluations in our patient to exclude the lung and the gastrointestinal lumen as a primary source of the malignancy. These tests were not particularly helpful, however. Instead, the most important diagnostic tool was tissue staining for neuroendocrine markers, which allowed a specific diagnosis to be made even in the absence of elevated serum hormone levels.

Conclusion

We conclude that the absence of clinically evident hormonal activity should not dissuade the physician from considering the possibility of a pancreatic islet cell primary tumor when a patient presents with metastatic neuroendocrine malignancy, even when there is no clear radiographic evidence of a pancreatic mass. Staining for neuroendocrine peptides can help the clinician make the diagnosis in such patients.

Acknowledgment

We thank Natalie Correia and Jessica Ancker for their constructive comments.

Accepted January 22, 2002.

References

(1.) Chastain MA. The glucagonoma syndrome: A review of its features and discussion of new perspectives. Am J Med Sci 2001;321:306-320.

(2.) Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. The glucagonoma syndrome: Clinical and pathologic features in 21 patients. Medicine (Baltimore) 1996;75:53-63.

(3.) Barazzoni R, Zanetti M, Tiengo A, Tessari P. Protein metabolism in glucagonoma. Diabetologia 1999;42:326-329.

(4.) Prinz RA, Dorsch TR, Lawrence AM. Clinical aspects of glucagon-producing islet cell tumors. Am J Gastroenterol 1981;76:125-131.

(5.) Reyes-Govea J, Holm A, Aldrete JS. Response of glucagonomas to surgical excision and chemotherapy: Report of two cases and review of the literature. Am Surg 1989;55:523-527.

(6.) Patel N, Chiang P, Krasnow AZ, Carrera GF, Komoroski RA, Isitman AT, et al. Skeletal metastasis of malignant glucagonoma mimicking avascular necrosis of the hip: Scintigraphic and MRI correlation. Clin Nuci Med 1993;18:70-72.

(7.) Staren ED, Steinecker GA, Gould VE. A glucagon-secreting pancreatic alpha islet cell tumor presenting as spinal cord compression. J Surg Oncol 1987;35:249-252.

(8.) Boden G. Glucagonomas and insulinomas. Gastroenterol Clin North Am 1989;18:831-845.

(9.) Hashimoto M, Watanabe G, Nakamura T, Kajiyama Y, Tsurumaru M. Clinically silent pancreatic glucagonomas discovered in resected specimens by immunohistochemistry. Surgery 1997;122:632-633.

(10.) Mozell E, Stenzel P, Woltering EA, Rosch J, O'Dorisio TM. Functional endocrine tumors of the pancreas: Clinical presentation, diagnosis, and treatment. Curr Probi Surg 1990;27:301-386.

(11.) Haga Y, Yanagi H, Urata J, Inada M, Shimada S, Nitahata N, et al. Early detection of pancreatic glucagonoma. Am J Gastroenterol 1995;90:2216-2223.

(12.) De Giorgio R, Migliori M, Lalli S, Montini GC, Gullo L, Corinaldesi R, et al. Asymptomatic glucagonoma presenting with an isolated hepatic nodule. Hepatogastroenterology 1998;45:1093-1096.

(13.) Hainsworth JD, Johnson DH, Greco FA: Poorly differentiated neuroendocrine carcinoma of unknown primary site: A newly recognized clinicopathologic entity. Ann Intern Med 1988;109:364-371.

(14.) Kirshbom PM, Kherani AR, Onaitis MW, Feldman JM, Tyler DS. Carcinoids of unknown origin: Comparative analysis with foregut, midgut, and hindgut carcinoids. Surgery 1998;124: 1063-1070.

(15.) O'Byrne KJ, Goggins MG, McDonald GS, Daly PA, Kelleher DP, Weir DG. A metastatic neuroendocrinc anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome: Assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with (111) In-pentetreotide. Cancer 1994;74:2374-2378.

(16.) Friesen SR, Hermreck AS, Mantz FA Jr. Glucagon, gastrin, and carcinoid tumors of the duodenum, pancreas, and stomach: Polypeptide "apudomas" of the foregut. Ant J Surg 1974;127:90-101.

RELATED ARTICLE: Key Points

* Pancreatic islet cell neoplasms can be hormonally silent.

* Certain pancreatic islet cell neoplasms, such as glucagonomas, are biologically aggressive and can metastasize widely.

* The absence of a pancreatic mass does not exclude the diagnosis of a pancreatic islet cell tumor. In such cases, cytologic staining for peptide hormones can help to determine the origin of the tumor.

Case Report

A 38-year-old, previously healthy woman presented to the emergency department with progressive low back pain of 3 months' duration. The pain had started insidiously but had become increasingly severe and had begun to radiate to the flanks, buttocks, and thighs bilaterally. The patient reported no changes in bowel or bladder control, and she denied fever and weight loss. There was no history of trauma, strenuous lifting, or recent pregnancy.

The patient appeared thin but not cachectic. Vital signs were unremarkable. No gross adenopathy was noted. The lungs were clear. There were no breast nodules. The cardiac examination was normal. The abdomen was nontender, and there was no palpable organomegaly. She had normal anal sphincter tone, and her stool was negative for occult blood. There was percussion tenderness of the lumbar spine, but motor function and reflexes were normal in the lower extremities. No skin rashes or oral lesions were present.

Serum chemistry values were notable for an elevated alkaline phosphatase level (239 U/L), but the patient's hepatic transaminase levels were normal. Levels of total and conjugated bilirubin, calcium, glucose, and albumin also were normal, as was the complete blood cell count. Computed tomographic scans of the abdomen and pelvis showed numerous hepatic lesions consistent with metastases, as well as an irregnlar mass in the region of the pancreas (Fig. 1). Abdominal ultrasonograms suggested that the apparent mass was, in fact, peripancreatic adenopathy, with nodes up to 3 cm in diameter. Magnetic resonance imaging scans of the spine showed a destructive lesion in the second lumbar vertebra with soft tissue extension compressing the spinal cord (Fig. 2). A whole-body bone scan demonstrated diffuse osseous metastases to the upper and lower extremities as well as the axial skeleton. The patient's upper and lower gastrointestinal endoscopic and pelvic ultrasonographic examinations were normal. A computed tomographi c scan of the chest showed bilateral axillary lymphadenopathy but no mass lesions in the lungs.

Ultrasonography-guided fine-needle aspiration of a peripancreatic lymph node was performed, and the cellular aspirate was diagnostic of a low-grade neuroendocrine neoplasm. Staining was positive for chromogranin A (a universal marker for neuroendocrine granules) and also was focally positive for glucagon (Fig. 3) but negative for serotonin, pancreatic polypeptide, and gastrin. Serum chemistry tests showed mild hypergastrinemia (106 pg/ml), but the glucagon level was normal (25 pg/ml), as were the levels of pro-insulin, somatostatin, and pancreatic polypeptide. A 24-hour urine collection showed no increase in 5-hydroxyindoleacetic acid level.

Because of the widespread metastases, the patient was deemed a poor surgical candidate. She underwent radiotherapy to the spine and to painful lesions in the right humerus and left femur, and she was treated with systemic chemotherapy consisting of doxorubicin and streptozocin. After 1 year of follow-up, the patient had progression of her metastases. She was continuing to undergo palliative care and remained free of systemic evidence of excess glucagon secretion.

From the Departments of Internal Medicine and Pathology, Cleveland Clinic Foundation, OH.

Reprint requests to Daniel J. Brotman, MD, Department of General Internal Medicine/E13, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Email: [e-mail]

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