Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1904
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 6310-6315
Copyright © 2005 by The Endocrine Society
Duodenal Somatostatinoma Associated with Diabetic Ketoacidosis Presumably Caused by Somatostatin-28 Hypersecretion
Dol Mi Kim,
Chul Woo Ahn,
Kyung Rae Kim,
Soon Won Hong,
Moon Suk Nam,
Bong Soo Cha,
Sung Kil Lim,
Hyun Chul Lee and
Eun Jig Lee
Departments of Endocrinology (D.M.K., C.W.A., K.R.K., B.S.C., S.K.L., H.C.L.) and Pathology (S.W.H.), Yonsei University, College of Medicine, Seoul 120-752, Korea; Department of Endocrinology (M.S.N.), Inha University College of Medicine, Incheon 400-711, Korea; and Department of Endocrinology, Metabolism, and Molecular Medicine (E.J.L.), Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611
Address all correspondence and requests for reprints to: Chul Woo Ahn, M.D., Yongdong Severance Hospital, Yonsei University, College of Medicine, 146-92 Dogok-Dong, Kangnam-Ku, Seoul, Korea. E-mail: acw{at}yumc.yonsei.ac.kr.
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Abstract
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Context: Extrapancreatic somatostatinoma is very rare and clinically distinguished from its pancreatic counterpart because somatostatinoma syndrome with mild diabetes is rare in extrapancreatic somatostatinoma because of poor secretion of somatostatin. Moreover, because somatostatin inhibits the secretion of insulin and glucagon simultaneously, true diabetic ketoacidosis (DKA) seldom ensues.
Patient: A 23-yr-old woman presented with DKA and an abdominal mass. A computed tomography scan showed a huge, encapsulated mass in a duodenal submucous portion. A high circulating level of somatostatin was detected (67.2 pmol/liter; reference range, 0.6–7.3 pmol/liter).
Intervention: The tumor mass was successfully removed with Whipple’s procedure, and the patient gradually recovered both clinically and biochemically.
Results: Immunohistochemical staining of the tumor tissue exhibited diffusely positive for somatostatin and somatostatin-28 but negative for insulin, glucagon, calcitonin, serotonin, and S-100.
Conclusion: As far as we know, this is the first case report of gastrointestinal somatostatinoma associated with DKA.
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Introduction
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SOMATOSTATIN WAS ORIGINALLY recognized as an inhibitor of GH isolated from the hypothalamus of a mammal in 1973 (1). Somatostatin is produced from D-type cells of the pancreas islet and gastrointestinal tract and in the central nervous system (2). The syndrome induced by excessive somatostatin secretion from somatostatinoma is characterized by steatorrhea, hypochlorhydria, anemia, cholelithiasis, and mild nonketotic hyperglycemia (3). Somatostatinomas are rare functioning neoplasms that usually arise in the pancreas and were first reported by Ganda et al. in 1977 (4). Extrapancreatic somatostatinoma was first reported by Alumets et al. in 1978 (5). Most extrapancreatic somatostatinomas were found near the descending part of the duodenum, and the ampulla and periampullary areas are known to be sites with a predilection to the tumor. In contrast to its pancreatic counterpart, they are rarely accompanied by somatostatinoma syndrome (6, 7). Because somatostatin simultaneously inhibits the secretion of insulin and glucagon from pancreatic islets, diabetic ketoacidosis (DKA) seldom develops, although mild hyperglycemia is occasionally observed in patients with somatostatinoma (8, 9). Jackson et al. (10) first described DKA in a patient with malignant somatostatinoma originating from the lung. We experienced a patient presenting with DKA and a large abdominal mass, which was proven to be a somatostatinoma producing somatostatin-28 predominantly. As far as we are aware, gastrointestinal somatostatinoma associated with DKA has not been reported previously.
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Case Report
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A 23-yr-old woman was admitted with an altered mental status. She had been suffering from polyuria and polydipsia and abdominal fullness with mild tenderness in the right upper quadrant for a month. One day before admission, she was administered enemas twice in a private clinic because of severe abdominal pain, and she became stuporous in several hours. She had no history of diabetes and had ingested neither alcohol nor medicines. On arrival, her blood pressure was 120/80 mm Hg, pulse rate 150 beats per minute, body temperature 37.5 C, and respiration rate 20 breaths per minute. She was 5.1 feet in height and weighed 105.8 pounds. She had lost 15.4 pounds of body weight over the past 6 months. Her mental status was stuporous, her tongue looked markedly dehydrated, and her skin turgor was reduced. Her conjunctiva was slightly pale, but the sclera was not icteric. On physical examination, a large and firm mass with mild tenderness was palpated under the right 11th intercostal space. Lung sounds were abnormal with crackles in both lower lung fields. Laboratory data on admission and after resolution of DKA were described in detail in Table 1
. Her liver functions and serum amylase and lipase levels were normal. The management of DKA was promptly started, and the ketoacidosis was corrected within 48 h with insulin and fluid replacement. A chest x-ray revealed diffuse infiltrations in both lower lobes of the lungs. Upper gastrointestinal endoscopy showed multiple duodenal ulcers of an active stage and exterior compression in the cardiac portion of the stomach. An endoscopic fine-needle aspiration biopsy of the expansile mass was performed. Hypotonic duodenography also disclosed a large mass arising from the duodenum, pushing the second portion of the duodenum to the front and left (Fig. 1A). A computed tomography scan subsequently confirmed an oval-shaped, encapsulated mass measuring 12 x 8 x 7 cm, with a bleeding necrosis in its center, which was separated from the pancreatic head in a duodenal submucous portion. No gallstone was found. Neither abdominal lymphadenopathy nor liver metastasis was observed (Fig. 1B). On the 7th admission day, blood samples were drawn to determine the biochemical characteristics of the abdominal mass (Table 1). Plasma glucagon (RIA, glucagon double antibody; Diagnostic Products Corp., Los Angeles, CA) was not elevated. A high circulating level of somatostatin (somatostatin RIA kit; Diagnostic Products) was detected, which persisted until the complete resection of the tumor was performed. Serum gastrin (gastrin RIA kit; Diagnostic Products) and serotonin (serotonin RIA kit; Diagnostic Products) levels were within normal range. Serum and urine catecholamine levels were normal. Fasting serum insulin and C-peptide (human RIA kit; Linco Research, Inc., St. Charles, MO) were within normal range. On the 18th day of admission, a Whipple procedure was performed, and the encapsulated tumor mass was successfully removed. No metastasis was found. Insulin was administered at 44 IU per day preoperatively, reduced to 20 IU per day immediately after the operation, and then gradually tapered off. After the resection of the primary tumor, the patient recovered rapidly. An oral glucose tolerance test (OGTT) conducted on the 12th postoperative day was normal. The patient was discharged without any medicine. Her fasting and postprandial plasma glucose levels measured on the 60th postoperative day were normal. The patient has remained well throughout the subsequent 11-yr follow-up period with neither clinical symptoms nor evidence of recurrence.
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FIG. 1. Radiological findings of the tumor. A, Hypotonic duodenography disclosed a large mass arising from the duodenum, pushing the second portion of the duodenum to the front and left. B, Computed tomography scan showed a 10-cm mass of a duodenal origin in an anterior aspect of vena cava with leftward displacement of pancreatic head and anterior displacement of gastric antrum and gall bladder with dilatation of a biliary tree.
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Methods and Results
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Pathology and immunohistochemistry
The study protocol using the patient’s samples was approved by the ethical committee of Yonsei Medical Center, and informed consent was obtained from the patient for publication. Grossly, the huge mass had a bleeding necrosis in its center and was entirely encapsulated (Fig. 2A). By light microscopy, the tumor tissue had an abundant, thick vascular web that was occasionally accompanied by bleeding. Polygonal tumor cells contained fine secretary granules within the cytoplasm and a centrally located phosphor-containing nucleus (Fig. 2, B and C). For immunohistochemical staining of the tumor tissue, we used three kinds of antibodies: anti-somatostatin made against the whole protein sequence of somatostatin from MLSCRLQCALAALS, anti-somatostatin-28 from SANSNPAMAPRERK, and anti-somatostatin-14 from AGCKNFFWKTFTSC. Immunohistochemical results exhibited diffusely positive reactions for somatostatin antibody (rabbit polyclonal; Zymed Laboratories, Inc., San Francisco, CA) (Fig. 2D) that can detect both somatostatin-14 and somatostatin-28. Strong positivity was also obtained using antibodies (rabbit polyclonal antibodies specific for somatostatin-14 and somatostatin-28; Advanced Targeting Systems, San Diego, CA) against somatostatin-14 (Fig. 2E) and somatostatin-28 (Fig. 2F). Therefore, an antibody against somatostatin-14, which was a part of somatostatin-28, was also able to detect somatostatin-28. However, anti-somatostatin-28 detected only somatostatin-28, not somatostatin-14. Negative reactions for insulin, glucagon, calcitonin, serotonin, and S-100 (Dako Corp., Carpinteria, CA) were observed (data not shown).
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FIG. 2. Pathological findings of the tumor. A, A gross examination of the resected specimen showed a brown-colored bleeding necrosis in the center of the well-encapsulated mass. B, Hematoxylin and eosin staining (H&E) showed that a huge well-demarcated mass is located beneath the duodenal mucosa. The tumor is composed of cellular sheets, cords, and high vascular networks. Magnification, x40. C, The polygonal tumor cells show plump cytoplasm, low nucleus to cytoplasm ratio, and prominent nucleoli. Magnification, x400. D–F, Immunohistochemical stain (IH) showed strong positivity for somatostatin-14 (D; x400), somatostatin-28 (E; x400), and somatostatin (F).
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Analysis of DNA
Genomic DNA was isolated from paraffin-embedded tumor specimens as described previously (11). Five adjacent 10-µm sections were cut from a paraffin block and mounted on slides. The middle section was stained with hematoxylin-eosin and served to distinguish tumor tissue from normal surrounding tissue. Genomic DNA was also extracted from blood leukocytes of the patient. We screened a possible germline or somatic mutation in Gs (12), H-Ras, K-Ras (13), N-Ras, P53 (14), and MEN1 genes using DNA extracted from tumor tissue and blood leukocytes. PCR amplification was performed using specific primer sets to cover every exonic portion of each gene. Each PCR product was purified, and direct sequencing was performed using an ABI 3100 automated DNA sequencer (Perkin-Elmer, Foster City, CA). No mutation was found.
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Discussion
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There is known to be predilection for extrapancreatic somatostatinoma to arise in duodenum and ampulla of Vater (15, 16, 17). Although their histologies may be similar in many aspects, extrapancreatic somatostatinomas are less common and are distinguished in their hormonal expression and growth behavior from their pancreatic counterparts by frequent associations with type I neurofibromatosis (Von Recklinghausen’s disease), the presence of psammoma bodies, and the lower frequency of demonstrable metastases at the time of operation. Moreover, extrapancreatic somatostatinoma rarely secretes somatostatin, and even when it does, the serum somatostatin level is lower (most commonly 61.1–122.2 pmol/liter) compared with its pancreatic counterpart. Thus, it is seldom associated with a recognizable somatostatin syndrome (6, 7, 18). Whereas most cases of pancreatic somatostatinoma exhibit markedly elevated serum somatostatin levels (100 times higher than normal ranges), its extrapancreatic counterpart rarely secretes somatostatin (see supplemental table published on The Endocrine Society’s Journals Online web site, http//jcem.endojournals.org). As is shown in Table 2, plasma somatostatin level was measured to be relatively low in our case compared with those in the other three cases. It is unusual that such a mildly elevated plasma level of somatostatin (67.2 pmol/liter; reference range, 0.6–7.3 pmol/liter) caused DKA in this case. This might be because of the abrupt release of a large amount of somatostatin from a tumor mass with severe bleeding necrosis as is shown in Fig. 2A
. However, we could not measure the actual level of plasma somatostatin at the time of DKA. Tumor lysis-induced somatostatin release has been previously proposed as a possible precipitating factor for ketogenesis (19). A lower rate of clearance of the larger polypeptides somatostatin-28 from the circulation would also be a contributing factor (20). In addition, respiratory infection and severe dehydration were aggravating factors in the development of DKA. Osmotic diuresis caused by uncontrolled hyperglycemia and repeated enemas may have led to severe dehydration. Laboratory results such as elevated blood urea nitrogen and creatinine, hypernatremia, and increased serum hyperosmolarity reflect severe depletion of intravascular volume of the patient as a result of renal and gastrointestinal loss at the time of DKA. It is known that 30% of DKA patients may experience hyperosmolarity (21). The patients with somatostatinoma may show mild hyperglycemia because elevated serum somatostatin inhibits insulin secretion. We found 12 reported cases with a wide range of glucose intolerance from impaired fasting glucose or glucose intolerance on OGTT to diabetes requiring insulin injection (see supplemental table). However, true DKA is rare because glucagon secretion is also suppressed simultaneously (8, 9). Nevertheless, DKA was reported in two cases of pancreatic somatostatinoma (19, 22) and in one case of pulmonary somatostatinoma with liver metastasis (10) (Table 2). In the latter case, serum insulin and C-peptide were markedly suppressed [14.0 pmol/liter (normal range, 36–179 pmol/liter) and <0.08 nmol/liter (normal range, 1.50–1.06 nmol/liter), respectively], but plasma glucagon was not suppressed below normal range [98.0 ng/liter (normal range, 50–200 ng/liter)]. Because we did not measure the levels of serum insulin and C-peptide and plasma glucagon at the time of DKA, we could not observe the same direction of hormonal responses leading to DKA. Somatostatin peptide hormone is in two biologically active forms (14 and 28 residues), which are derived from a large precursor, prosomatostatin. Somatostatin-14 and somatostatin-28 were found to have different actions and tissue distributions (23). Somatostatin-14 is distributed in the central nervous system, pancreas, and neurons of the upper gastrointestinal tract. It inhibits glucagon, gastric acid, visceral blood flow, and intestine movement more selectively than somatostatin-28 does (24). On the other hand, somatostatin-28 is found in the central nervous system and gastrointestinal mucosa and inhibits insulin, GH, and TSH more selectively than somatostatin-14 does (25). Because somatostatin-28 suppresses insulin selectively while sparing glucagon, it would be conceivable that DKA could be preferentially developed in the situation of somatostatin-28 hypersecretion. Immunohistochemical stain results using specific antibody showed strong positivity for somatostatin-28, suggesting that the tumor of our patient may produce somatostatin-28 predominantly. In case of somatostatinoma predominantly producing somatostatin-14, immunohistochemical stain using somatostatin-28 antibody would be entirely negative. However, we could not confirm the elevation of the specific level of somatostatin-28 in the plasma of our patient. A previous case of malignant pulmonary somatostatinoma associated with DKA was found to produce somatostatin-28 predominantly, which was confirmed on chromatographic results (10). In summary, we report a case of duodenal somatostatinoma associated with DKA presumably caused by somatostatin-28 hypersecretion. DKA was reversed promptly by insulin administration and rehydration, and diabetes was cured by surgical removal of the tumor. Although several reports have documented the development of mild diabetes in patients with duodenal somatostatinomas, to the best of our knowledge, this is the first report of the full manifestation of DKA associated with duodenal somatostatinoma.
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Acknowledgments
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We thank Tom Kotlar for automated DNA sequencing and Min-Ho Lee and Kevin Kordi for the assistance in DNA analysis.
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Footnotes
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First Published Online August 16, 2005
Abbreviations: DKA, Diabetic ketoacidosis; OGTT, oral glucose tolerance test.
Received September 28, 2004.
Accepted August 5, 2005.
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References
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Abstract
Introduction
