Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2004-0825
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 575-580
Copyright © 2005 by The Endocrine Society
Giant Insulinoma: Case Report and Review of the Literature
Elizabeth A. Mittendorf,
Yao-Chang Liu and
Christopher R. McHenry
Department of Surgery, Uniformed Services University of the Health Sciences (E.A.M.), Bethesda, Maryland 20762; and Departments of Pathology (Y.-C.L.) and Surgery (C.R.M.), MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109
Address all correspondence and requests for reprints to: Dr. Christopher R. McHenry, Department of Surgery, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, Ohio 44109. E-mail: cmchenry{at}metrohealth.org.
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Abstract
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An insulinoma is a rare pancreatic endocrine tumor that is typically sporadic, solitary, and less than 2 cm in diameter. Fewer than 5% of insulinomas are larger than 3 cm. Ninety percent or more of all insulinomas are benign. Larger tumors are more likely to be malignant. We report a case of a giant pedunculated insulinoma, measuring 9 cm in diameter and weighing 100 g, with amyloid deposits accounting for 70% of the tumor volume. At the time of operation, no local invasion or metastatic disease was identified. On pathological evaluation, the tumor was classified as an insulinoma of uncertain biological behavior. In addition to describing the clinical presentation and operative findings, criteria for determining malignancy are outlined, a detailed pathological description is presented, and the 2000 World Health Organization Classification for Pancreatic Endocrine Neoplasms is reviewed.
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Introduction
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PANCREATIC ENDOCRINE TUMORS are rare lesions, with a reported incidence of four cases per 1 million patient-yr (1). Of these lesions, insulinomas are the most common. The majority of patients diagnosed with an insulinoma are between 30 and 60 yr of age, with women accounting for 59% (2, 3). Most insulinomas are sporadic in origin. In two series, 7.6% and 12% of patients with insulinoma had multiple endocrine neoplasia type I syndrome (1, 4) Insulinomas are more likely to be multiple in patients with multiple endocrine neoplasia type I (1, 4).
Patients with insulinoma have symptoms of hypoglycemia resulting from neuroglycopenia and increased catecholamine release. Neuroglycopenic symptoms are most common, including anxiety, dizziness, lightheadedness, personality changes, unusual behavior, confusion, incoherence, blurred vision, seizures, and coma. Sympathoadrenal signs and symptoms, such as palpitations, tre-mulousness, diaphoresis, and tachycardia, may also be present and are due to catecholamine release in response to low serum glucose levels (5). Surgical excision is the treatment of choice and is curative in most cases. At the time of surgery, the majority of these lesions are found to be solitary, equally distributed throughout the pancreas, and less than 2 cm in diameter. In a review of the experience at University of Michigan, Pasieka et al. (6) reported that 24% were less than 1 cm, 42% were 1–2 cm, 30% were 2–3 cm, and only 4% larger than 3 cm. Those that are larger than 3 cm are more likely to be malignant, with local invasion or metastases to the peripancreatic lymph nodes and liver. We report a patient with a 9-cm insulinoma comprised of a disproportionate amount of amyloid without evidence of local invasion or metastatic disease. The case review was approved by the institutional review board at MetroHealth Medical Center.
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Case Report
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A 65-yr-old woman was seen in the emergency department with the acute onset of lightheadedness, chills, diaphoresis, palpitations, and shakiness. A serum glucose level determined in the Emergency Department was 28 mg/dl (1.55 mmol/liter; normal range, 68–110 mg/dl; 3.7–6.1 mmol/liter). She was given 10% dextrose iv, and her symptoms resolved. The patient reported that she had experienced similar symptoms, but of lesser severity, for approximately 3-yr duration. She typically experienced the symptoms from 1000–1300 h during the day, although she was occasionally awakened at night with symptoms. She also reported a recent 20-lb weight gain. She denied any galactorrhea or visual changes. She was discharged from the emergency department, and her work-up was completed as an out-patient.
Her past medical history was significant for osteoporosis and hypercholesterolemia, for which she was taking Fosamax and Lipitor. She also reported intermittent hypertension. She had previously undergone a total abdominal hysterectomy and bilateral salpingooophorectomy for a benign ovarian mass and a lumpectomy and radiation therapy for breast cancer. Her family history was remarkable for a daughter with hypothyroidism and a maternal grandmother who had diabetes mellitus. Her father died at age 45 yr of Bright’s disease, and her mother died at age 43 yr of a cerebral hemorrhage. There was no family history of hyperparathyroidism, ulcer disease, or hypoglycemia.
The physical examination was unremarkable. She was a well developed and well nourished woman, with no nipple discharge and a normal visual field exam. Her abdomen was soft and nontender, with no palpable masses or organomegaly.
The results of her subsequent laboratory evaluation are detailed in Table 1
. Of note, the patient was observed in an office setting after cessation of any oral intake at 2000 h the night before the office visit. The first, second, and third glucose, insulin, and C peptide levels represent values obtained after 12, 18, and 20 h of fasting. A diagnosis of insulinoma was made, and a computed tomogram of the abdomen was obtained. Spiral axial 1-mm collimated images were obtained through the pancreas in early arterial phase after a 100-cc injection of iv contrast. Oral contrast material was also administered. A large, heterogeneous enhancing mass associated with the distal tail of the pancreas (Fig. 1) was identified. There was no associated lymphadenopathy. The liver appeared normal.
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FIG. 1. Computed tomographic image of the abdomen, demonstrating a large heterogeneous enhancing insulinoma arising from the tail of the pancreas.
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At operation, a 9 x 6.5 x 4-cm pedunculated tumor, weighing 100 g, was resected from the tail of the pancreas (Fig. 2). There was no evidence of gross invasion, abnormal lymph nodes, or liver metastases. Pathological evaluation revealed a well differentiated insulinoma with extensive amyloid deposition occupying approximately 70% of the tumor volume (Fig. 3A). The amyloid was confirmed by a Congo Red stain as well as by demonstration of apple green birefringence under polarized light. The protein component of the amyloid was islet amyloid polypeptide, otherwise known as amylin. The tumor had more than 2% Ki-67-positive cells/10 high powered fields (HPF; Fig. 3B), and less than one mitosis per 10 HPF. There was no local or microscopic vascular invasion. On electron microscopy, the amyloid deposits consisted of a disordered meshwork of nonbranching rigid fibrils (Fig. 3C). Immunohistochemical studies using an immunoperoxidase method revealed that nearly all of the neoplastic cells were strongly positive for the neuroendocrine markers synaptophysin (Fig. 4A) and chromogranin. In addition, 50% of the tumor cells were positive for insulin (Fig. 4B), 30% for pancreatic polypeptide (Fig. 4C), 15% for glucagon, and 5% for somatostatin. The tumor was classified as an insulinoma of uncertain biological behavior based on the 2000 World Health Organization Classification for Pancreatic Endocrine Neoplasms (Table 2).
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FIG. 3. Microscopic features of the excised insulinoma. A, Tumor cells in a broad anastomosing trabecular pattern within a background of abundant pink homogeneous amyloid (x400 magnification); B, immunoperoxidase stain for Ki-67 cells, demonstrating three tumor cells with positive nuclear staining pattern (x200 magnification); C, electron micrograph, demonstrating rigid, nonbranching filaments of amyloid measuring 7–10 mm in diameter.
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FIG. 4. Histological sections of the insulinoma with immunohistochemical demonstration of almost all the tumor cells with immunoreactivity to the neuroendocrine marker synaptophysin (A), 50% of the tumor cells with immunoreactivity to insulin antibody (B), 30% of the tumor cells with immunoreactivity to pancreatic polypeptide antibody (C), and none of the tumor cells with immunoreactivity for calcitonin (D; control).
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The patient reported complete resolution of her symptoms. Her postoperative course was complicated by a low output pancreatic fistula, which closed 1 wk after surgery. She developed hyperglycemia in the postoperative period, with serum glucose levels as high as 303 mg/dl (16.8 mmol/liter; normal range, 3.7–6.1 mmol/liter). At her 6-wk follow-up, her fasting blood glucose and insulin levels were 120 mg/dl (6.66 mmol/liter) and 95.4 pmol/liter (normal range, 6–144 pmol/liter), respectively. A routine follow-up computed tomogram of the abdomen was obtained 6 months postoperatively and showed no evidence of recurrent disease.
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Discussion
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We report a case of a giant insulinoma measuring 9 cm and weighing 100 g. It was pedunculated and attached to the tail of the pancreas, rather than within the gland. The tumor expressed multiple hormones, including glucagon, pancreatic polypeptide, and somatostatin, in addition to insulin, a phenomenon that is often reported with pancreatic endocrine neoplasms (7, 8, 9). There was no evidence of local invasion or metastases to the regional lymph nodes or liver. The majority of patients with insulinomas have lesions that are 1–2 cm in size, with 96% being less than 3 cm (6). The mean tumor size of insulinomas found in three of the largest reported series was 1.5 cm, with a range of 0.1–7.0 cm (3, 10, 11).
The large size and weight of the tumor was related to the unusually extensive proportion of amyloid. Amyloid deposits have been demonstrated in more than 50% of insulinomas, but not to the extent present in our patient’s tumor (12, 13). The major component of the amyloid of an insulinoma is a 37-amino acid polypeptide known as islet amyloid polypeptide or amylin. Islet amyloid polypeptide has been observed within the tumor cells and the stroma surrounding the islet cells of patients with an insulinoma as well as in the stroma surrounding the islet cells of patients with insulinomas and patients with type II diabetes mellitus (12, 13). Overexpression of islet amyloid polypeptide, with aberrant processing and secretion by abnormal ß-cells of the insulinoma, is postulated to be the cause of amyloidogenesis (13).
Tumors larger than 3 cm raise concern for malignancy. The diagnosis of malignancy is based on the presence of metastases to the liver or regional lymph nodes or gross evidence of local invasion. In a review of malignant insulinomas, Danforth et al. (14) identified 62 cases: 17 from the NIH and 45 others reported in the literature. Thorough pathological data were available for 14 of the patients treated at the NIH. The average tumor size was 4.7 ± 0.6 cm. There were 11 lesions more than 3 cm in diameter, including two that were 7.0 cm and one that was 9.0 cm. Data regarding tumor size were available for 25 of the 45 cases found in their literature review, and the average size in this group was 7.1 ± 0.8 cm (14). Additional review of the world literature identifies only three reported cases of insulinomas more than 9 cm in size, all of which were benign by traditional criteria (15, 16, 17).
In addition to the large tumor size, more than 2% of the tumor cells/HPF were Ki-67-positive cells. Measurement of the percentage of Ki-67 cells provides an assessment of the tumor’s proliferative index. The patient’s tumor was classified as an insulinoma of uncertain biological behavior according to the 2000 World Health Organization Classification for Pancreatic Endocrine Neoplasms. This new clinicopathological classification of neuroendocrine tumors was adopted because it combines an assessment of the clinical syndrome as well as tumor morphology.
In devising this new classification system, it was recognized that classic histopathological criteria, such as atypia, were of limited value in predicting the behavior of neuroendocrine tumors of the pancreas. Several new histopathological criteria were considered: 1) tumor size; 2) local invasion; 3) structural atypia with prevalence of broad solid areas; 4) necrosis; 5) cellular atypia with high nuclear cytoplasmic ratio, irregular distribution of chromatin, and prominent nucleoli; 6) more than two mitoses per 10 HPF; 7) more than 2% Ki-67-positive tumor cells; 8) perineural or angioinvasion; 9) cellular dedifferentiation, as assessed by loss of chromogranin A immunoreactivity; and 10) nuclear p53 protein accumulation detected by immunohistochemistry (18). Our patient’s tumor displayed the favorable finding of fewer than one mitosis per 10 HPF; however, the finding of more than 2% Ki-67-positive tumor cells indicates an increased risk of malignant behavior; therefore, the tumor was classified as an insulinoma of uncertain biological behavior. Despite new histopathological criteria, there are no conclusive histological criteria or histochemical markers that reliably predict biological behavior, and the definitive diagnosis of malignant insulinoma is still based on the presence of metastases or gross evidence of local invasion (2).
Our patient displayed several characteristics typical for insulinomas. She admitted to a 3-yr history of symptoms similar to those that prompted her presentation to the emergency department. It is not uncommon for patients to have symptoms for several months to years before diagnosis, in part because the diagnosis is not entertained by clinicians. This is presumed to be due to the rarity of pancreatic endocrine tumors.
In 1935, Whipple and Franz (19) described a triad of clinical findings that were unique to patients with insulinoma: symptoms of hypoglycemia, a plasma glucose level of 45 mg/dl (2.5 mmol/liter) or less when symptoms of hypoglycemia occurred, and relief of symptoms with the administration of glucose. More recently, Service (20) recommended the following biochemical criteria to establish a diagnosis of insulinoma in the absence of renal insufficiency: an insulin level of 36 pmol/liter or more as measured by RIA or of 18 pmol/liter or more as measured by an immunochemiluminescence assay, a C peptide level of 200 pmol/liter or more, and a proinsulin level of 5 pmol/liter or more in a patient with a serum glucose level of 45 mg/dl (2.5 mmol/liter) or less, a negative plasma sulfonylurea screen (including repaglinide), and negative insulin antibodies. Vezzosi et al. (21), using a modern insulin-specific immunoradiometric assay, have documented insulin levels below 18 pmol/liter in patients with symptomatic hypoglycemia of 45 mg/dl or less from small insulinomas. They concluded that insulin levels are dependent on the assay employed and its cross-reactivity with proinsulin, and they emphasized that concomitant measurement of C peptide levels is mandatory for establishing a diagnosis of insulinoma (21). In most patients with insulinoma, a diagnosis is established by a supervised fast during which simultaneous measurements of glucose, insulin, and C peptide are obtained. On presentation, our patient had a serum glucose level of 28 mg/dl (1.55 mmol/liter) and typical symptoms of hypoglycemia that were relieved by iv glucose. Subsequent biochemical indices obtained during a 20-h fast confirmed the diagnosis of insulinoma.
The imaging modalities used for localization of an insulinoma remain an area of debate. Clinicians who do not routinely perform preoperative localization cite studies that document a 30–35% failure rate with noninvasive imaging studies and report that those tumors that are localized preoperatively are easily identified by palpation or intraoperative ultrasound (22). Intraoperative palpation and ultrasound are the gold standards for localizing an insulinoma, with a reported success rate of 96–100%.
It is our practice to routinely perform a spiral computed tomographic scan of the abdomen in patients with functional pancreatic endocrine tumors. Although reported sensitivities are suboptimal, ranging from 20–40%, valuable information concerning the primary tumor location, the presence of metastatic disease, and potential resectability may be obtained (6, 10, 23). If liver metastases are identified, plans are made for resection. In general, a wedge resection of hepatic metastases is performed. Hepatic resection for metastatic neuroendocrine malignancies has been found to be safe and effective for palliation (24). Because of the rarity of insulinomas and our relative inexperience with intraoperative ultrasound, we would perform hepatic venous insulin sampling after administration of intraarterial calcium to help localize an occult insulinoma before proceeding with laparotomy. This technique is very sensitive in localizing insulinomas, which are typically highly vascular, and has been reported to be positive in up to 75% of cases (25). Some centers use preoperative endoscopic ultrasound, which has reported accuracy rates of 60–90% (26). Lesions in the tail may be missed using endoscopic ultrasound; however, these lesions are usually easily identified intraoperatively (27). Approximately 40% of all insulinomas are not localized preoperatively, and between 3% and 10% remain occult even after intraoperative palpation and the use of intraoperative ultrasound (3, 4).
In conclusion, this case report emphasizes some unusual features of an insulinoma of which a clinician should be aware, including an extremely large tumor size in the absence of definite features of malignancy; the inordinate deposition of amyloid, which accounted for 70% of the tumor volume; and the pedunculated nature of the tumor, which arose from the surface of the pancreas rather than from within the parenchyma. The goal of treatment of a patient with an insulinoma is to identify and excise the primary tumor and, when possible, all metastatic disease. Follow-up computed tomographic scanning of the abdomen is recommended for insulinomas of uncertain behavior to evaluate subsequent development of recurrent or metastatic disease. In the absence of neuroglycopenic symptoms, it is our approach to obtain a follow-up computed tomogram of the abdomen at 6 and then 12 months. Thereafter, computed tomography is performed only if patients become symptomatic.
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Footnotes
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First Published Online November 2, 2004
Abbreviation: HPF, High powered field.
Received May 3, 2004.
Accepted October 22, 2004.
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References
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Abstract
Introduction
