Malignant insulinoma: spectrum of unusual clinical features

Abstract

Background

Malignant insulinoma occurs in a few patients with insulinoma. Due to the small sample of patients, there are little data regarding their clinical manifestation as well as the preferred treatment modalities. The aims of the current study were to summarize the National Institutes of Health experience during the last two decades and to conduct a critical review of the current literature.

Methods

The authors identified 10 patients with metastatic insulinoma.

Results

The patients presented with four patterns of clinical behavior. First, four patients presented with lymph node metastasis and, after surgical excision, maintained a prolonged tumor-free survival. Second, four patients presented with metastatic disease to the liver, which appeared years after the initial diagnosis and presumed curative surgery. Third, one patient presented with a large α-fetoprotein-secreting liver mass. Finally, 9 of the 10 patients had a prolonged survival. Various treatment modalities were used to control hypoglycemia. Short-term benefits were most often achieved with embolization and diazoxide. Less successful modalities included radiofrequency ablation, radical debulking surgery, verapamil therapy, octreotide therapy, and chemotherapy.

Conclusions

The current study, as well as others, suggested that metastatic insulinoma may have a variable natural history. After the initial surgical resection, the biology of the tumor, rather than any treatment modality, was most likely the major determinant of long-term survival. Published 2005 by the American Cancer Society.^*

Two features dominate the clinical characteristics of the various functional islet cell tumors of the pancreas, i.e., the hormone they secrete¹ and their propensity to metastasize.² Because there are no specific morphologic, biochemical, or genetic features that distinguish benign from malignant tumors, this distinction can only be made by the presence of metastasis. Although most islet cell tumors have malignant characteristics defined by metastases, insulinoma is an exception because approximately 90% are benign adenomas.^3–5 Insulinoma is relatively rare, with approximately 4 cases per million person-years and < 10% of the cases are malignant.^3,5 Therefore, information on the clinical behavior of malignant insulinoma is limited.

In 1984, we reviewed the course of 17 patients treated at the Warren Grant Magnuson Clinical Center, National Institutes of Health (NIH; Bethesda, MD), as well as an additional 45 patients identified in the literature.⁶ Since that time we have had the opportunity to observe 10 patients (5 from the original publication and 5 additional patients) who present with very unusual clinical behavior that offers some guidance to the management of patients with malignant insulinoma. The aims of the current report are to describe these patients and to summarize the possible approaches to therapy for this rare condition.

Materials and Methods

Patients

Previously, we reported on 17 patients with malignant insulinoma studied at the Warren Grant Magnuson Clinical Center until 1982 and compared these data with 45 patients identified in the literature.⁶ Of the 17 NIH patients, 11 had died by the time of the report and 1 died shortly afterward. The current study focuses on the follow-up of those five surviving patients, as well as five new patients treated until the present. These patients are part of a cohort recruited to a protocol approved by the institutional review board of the National Institute of Diabetes, Digestive and Kidney Diseases, NIH. Patients were admitted to the Warren Grant Magnuson Clinical Center. All patients received a complete history and physical examination, routine blood examination, and urine chemistries as per our previously published guidelines.⁴

Laboratory Values

Glucose levels and other standard laboratory values were determined in the Warren Grant Magnuson Clinical Center laboratory. Methods for determining insulin and proinsulin levels have been reported.⁷ A pathologist evaluated tissue samples obtained during surgery or biopsy. This included both routine and immunochemical staining.

Case Reports

We identified 10 patients with metastatic insulinoma (Table 1). Six had liver metastasis and four had lymph node metastasis. None of the patients had evidence of the multiple endocrine neoplasia syndrome.

Table 1. Clinical Course of Patients with Malignant Insulinoma.

Patient no.	Age of presentation to NIH/gender	Age of diagnosis (yrs)	Time from diagnosis to indication of metastatic disease	Duration of symptoms till first diagnosis	Initial tumor location	Initial treatment	Metastatic location	Treatment of metastatic disease	Follow-up
1	59/male	47	12 yrs	17 yrs	1st surgery: head 15-mm 2nd surgery: head 3.5-cm	Enucleation, whipple	Liver, pancreas	Chemotherapy, embolization, radiofrequency, diazoxide	Alive 20 yrs after initial diagnosis
2	26/male	26	4 mos	6 yrs	Tail 0.2 ×-3-cm	Distal pancreatectomy	Liver	Diazoxide	Disease recurrence in liver at 4 mos; lived 30 yrs with disease; diazoxide
3	43/female	37	6 yrs	1 yr	Tail 1.5-cm; enucleation; distal nothing found	Enucleation, blind 2/3 distal pancreatectomy	Liver	Chemotherapy	Disease recurrence in liver at 6 yrs; 30 yrs after diagnosis; diazoxide
4	33/female	25	8 yrs	4 yrs	Head 2.6-cm	Enucleation	Liver	Diazoxide	Stable 3 yrs postmetastasis
5	29/female	29	4 yrs	6 mos	Head	Enucleation	1.5-cm lymph node and lesion near tail		Stable for 3 yrs with no treatment
6	82/female	82	At diagnosis	3 mos	Liver	Radiofrequency ablation	Liver	Radiofrequency ablation	Died 4 mos postablation
7	47/female	47	At diagnosis	5 yrs	Tail 3–4 cm from tail	Distal pancreatectomy	Lymph nodes		Alive 24 yrs after diagnosis
8	68/female	68	At diagnosis	3 yrs	Body-right of confluence of splenic and IMV 8 ×-6.5 ×-5-cm	Distal pancreatectomy	Lymph nodes		No disease recurrence; alive 25 yrs after diagnosis
9	30/male	30	At diagnosis	4 mos	Body-firmly attached to stomach 8 × 9 × 5.5 cm, 130 g	Distal pancreatectomy	Lymph nodes, vessels		No disease recurrence; alive 23 yrs after diagnosis
10	33/female	33	At diagnosis	1 mo	Body-superior border 2-cm; tail-inferior border 1.5-cm; tail -superior border 1.5-cm	Distal pancreatectomy	Lymph nodes		No disease recurrence, alive 10 yrs after diagnosis

NIH: National Institutes of Health; IMV: inferior mesenteric vein.

Patient 1

Patient 1 (Fig. 1) developed initial symptoms consistent with hypoglycemia in 1967 at the age of 30 years. In 1984, after a seizure, he was found to be hypoglycemic. The patient underwent a formal fast that resulted in hypoglycemia after 24 hours. He subsequently underwent an enucleation of a 15-mm tumor in the head of the pancreas. Pathologic evaluation was consistent with insulinoma. The patient was free from symptoms for approximately 4 years when he experienced recurrent symptoms. Two years later, he was found to have a 3.5-cm tumor in the head of the pancreas and underwent a pancreaticoduodenectomy (Whipple procedure) after which he was symptom free for approximately 3 years. Six years after the Whipple procedure, the patient developed recurrent, severe hypoglycemia that resulted in two episodes of coma. Diagnostic imaging confirmed metastatic insulinoma to the liver. The patient was initially treated with doxorubicin and streptozotocin without benefit. Symptoms abated in 1996 after three chemoembolizations with doxorubicin and continued treatment with diazoxide. In June 2000, surgical resection of tumor deposits and radio frequency ablation of hepatic lesions were performed because of recurrent hypoglycemia. In 2001, he participated in an experimental protocol at Louisiana State University using radiolabeled somatostatin⁸ and had an improvement in hypoglycemic symptoms lasting for approximately 18 months. In January 2003, glucose, insulin, and proinsulin levels were 90 mg/dL, 7.2 μU/mL, and 0.22 ng/mL, respectively. The patient lives at home and receives maintenance therapy with diazoxide, frequent meals, and intermittent intravenous glucose infusions. He recently enrolled in a second radiolabeled somatostatin protocol (unpublished data). The patient has survived 20 years after his initial surgery and 16 years have elapsed since liver metastases were first demonstrated.

Figure 1.

Clinical course of Patient 1. This time line of therapeutic approaches summarizes data for Patient 1. After his first 2 surgical treatments, the patient received chemotherapy with no effect, chemoemblolization with an approximately 18-month remission of hypoglycemia, debulking surgery and radiofrequency ablation with no effect, and finally an experimental radioactive somatostatin protocol⁸ with a period of disease remission of approximately 18 months. Diazoxide given over the past 6 years has lessened but not prevented hypoglycemia.

Patient 2

The patient initially presented at the age of 26 years to the NIH with symptoms of hypoglycemia of 6 years duration. Hypoglycemia was demonstrated on fasting and corrected by eating. An insulinoma was removed from the distal pancreas. Hypoglycemia persisted postoperatively and a second surgery was performed 3 months later. At that time, hepatic islet cell metastases were observed and he underwent a biopsy. The patient's symptoms were controlled with diazoxide. Sixteen years later, he underwent a cholecystectomy, and the liver nodules were again observed. The patient's weight increased steadily over the ensuing years to 147.7 kg. In the year before his death, he developed hyperglycemia and diazoxide was stopped. In his last year of life, he required insulin therapy for diabetes. The patient died 30 years after the initial diagnosis of insulinoma because of an acute myocardial infarction. Postmortem examination revealed numerous tumor nodules on the surface of the liver that ranged from 0.2–6 cm. Microscopically, the tumor cells stained strongly for insulin and chromogranin and weakly for pancreatic polypeptide and somatostatin. The staining for glucagon and gastrin was negative.

Patient 3

The patient initially presented at the age of 36 years with recurrent episodes of disorientation, hallucinations, and agitation. The diagnosis of insulinoma was confirmed with documented hypoglycemia in the setting of inappropriately elevated serum insulin levels. A 1.5-cm insulinoma was removed from the tail of the pancreas by enucleation. The patient did well for 5 years, after which time she experienced recurrent hypoglycemic episodes. At a second exploratory laparotomy, no tumor was found and a blind 2/3 distal pancreatectomy was performed. The patient remained hypoglycemic and a third exploratory procedure confirmed by biopsy the existence of liver metastasis. She was referred to the NIH at the age of 43 years. She was treated with streptozotocin with no beneficial effect. A regimen of verapamil 80 mg every 6 hours and diazoxide 100 mg every 6 hours was started with major relief from hypoglycemia. At age 46, she underwent a diagnostic fast while receiving diazoxide 300 mg with glucose values of 100 mg/dL and insulin of 30-35 μU/mL. However, while not receiving diazoxide at 17 hours of fasting her glucose level decreased to 38 mg/dL with an insulin level of 60 μU/mL. She was seen again at age 52 years while receiving diazoxide 400 mg and reported only 1 episode of hypoglycemia. A 14-hour diagnostic fast while receiving diazoxide therapy revealed a blood glucose level of 40 mg/dL and neuroglycopenic symptoms. The patient was next seen at age 72 years. She was working, feeling well, and had only occasional symptoms of hypoglycemia while receiving diazoxide 300 mg per day and her hemoglobin A1C was 7.2%. Thus, this patient with known liver metastasis has been receiving diazoxide for 30 years and has mild diabetes.

Patient 4

A 33-year-old woman reported symptoms compatible with hypoglycemia since age 21 years. Eight years before admission, she had a 2.6-cm neuroendocrine tumor enucleated from the head of the pancreas. She remained symptom free for the next 4 years when hypoglycemic symptoms reappeared. Before any therapy was administered, she became pregnant and her symptoms abated during the pregnancy. After the delivery of a normal baby, she again experienced hypoglycemic symptoms. Six months before her NIH admission, she underwent an extensive workup in another center. All noninvasive imaging studies were negative and upon exploration, no lesions were found in the pancreas or liver by palpation or intraoperative ultrasound. Subsequently, she underwent a liver biopsy, which was also negative. Six months later, she was admitted to the NIH and had fasting hypoglycemia and inappropriately elevated insulin concentrations. Again, all noninvasive imaging was negative. An arteriogram showed a delicate miliary pattern in the liver, which was identical to the 1 done 6 months previously. A selective angiography combined with a computed tomographic scan demonstrated liver lesions suggestive of malignancy (Fig. 2). A calcium-stimulated arteriogram localized a lesion in the pancreatic head. At exploration, no lesion was found in the pancreas by palpation or ultrasound. Several small flat lesions were observed on the surface of the liver. Biopsies of these lesions were positive for neuroendocrine tumor after pathologic evaluation (Fig. 3). No further surgery was done and the patient has been stable for the last 3 years while receiving diazoxide 300 mg per day with no additional hypoglycemic events.

Figure 2.

(A) T1-weighted gadolinium-enhanced axial magnetic resonance image scan of the liver was normal, without hepatic parenchymal signal abnormality or evidence of disease. (B) Selective common hepatic arterial injection during computed tomographic scan demonstrate multiple subcentimeter enhancing miliary nodules scattered throughout the hepatic parenchyma. Catheter shaft resides in the celiac axis.

Figure 3.

Metastatic insulinoma. This hepatic metastasis of insulinoma shows a trabecular and pseudoacinar architecture typical of neuroendocrine tumor. The nuclei are small and oval with minimal pleomorphism. Mitotic figures were not observed. Immunohistochemical staining showed that the tumor cells were positive for insulin and synaptophysin. (H & E, original magnification × 400.)

Patient 5

A 29-year-old woman presented with diagnostic findings consistent with insulinoma. She underwent laparotomy and an insulinoma was enucleated from the pancreatic head. She remained asymptomatic for 4 years, after which time hypoglycemic symptoms recurred. A calcium-stimulated angiography demonstrated a step up in the superior mesenteric artery (Fig. 4). She underwent a second laparotomy, at which time a 1.5-cm lymph node containing neuroendocrine tumor was found near the previous enucleation site. In addition, a metastatic tumor nodule < 3 mm was resected from the surface of the liver. After this procedure, the patient became asymptomatic and a 48-hour fast 6 weeks later revealed normal glucose and insulin levels. She has now been off medications and with no symptoms for 3 years.

Figure 4.

Ca++ arterial-stimulation venous sampling from the right hepatic vein.³⁹ Six separate arteries are selectively injected and blood specimens were collected from the right hepatic vein. Localizations are to the distribution of the superior mesenteric artery.

Patient 6

An 82-year-old female with severe fasting hypoglycemia presented with an 8-cm solitary mass in the dome of the liver (Fig. 5) and an α-fetoprotein (AFP) level of 40. The diagnosis of hepatoma with nonislet cell hypoglycemia was considered. The insulin and proinsulin levels were elevated and a needle biopsy of the mass demonstrated a neuroendocrine tumor. Percutaneous radiofrequency ablation normalized (Fig. 5) glucose levels, insulin levels decreased from 26 μU/mL to 14 μU/mL, proinsulin levels decreased from 10 μg/mL to 2 μg/mL, and AFP levels decreased from 41 to 23. However, 4 month later, the hypoglycemic symptoms recurred, and the patient elected not to undergo additional interventions because of other comorbidities.

Figure 5.

(A) T1-weighted gadolinium-enhanced axial magnetic resonance image (MRI) scan of the liver before ablation demonstrates an intermediate-signal solitary mass measuring > 9 cm in dimension. (B) T1-weighted gadolinium-enhanced axial MRI scan of the liver after ablation demonstrates a low signal within the central part of the mass representing devascularized coagulation necrosis, with an intermediate signal in the peripheral rim representing vascularized residual viable tumor.

Results

The current study involves 10 patients with proven malignant insulinoma who present 4 patterns of very unusual clinical behavior (Table 1).

Synchronous Lymph Node Metastases Only

Four patients (Patients 7, 8, 9, and 10) who met the diagnostic criteria for insulinoma underwent laparotomy for removal of the neuroendocrine tumor. No evidence of metastatic disease was found at the time of initial operation but for each patient, a neuroendocrine tumor metastasis was found in lymph nodes removed with the specimen. These four patients have now been followed for 15–26 years with no further treatment and no evidence of recurrent disease. One of these patients followed for 25 years had a primary tumor that measured 9 cm in dimension and this patient remains asymptomatic (Patient 8, Table 1).

Prolonged Interval between Primary Tumor Removal and Evidence of Metastatic Disease

Four patients (Patients 1, 3, 4, and 5) met the diagnostic criteria for insulinoma and underwent laparotomy. In three of these four patients, a neuroendocrine tumor was enucleated from the pancreatic head and in the fourth patient the tumor was removed from the body of the pancreas by distal pancreatectomy. In each of the patients there was no additional evidence of macroscopic or microscopic disease. All 4 patients remained symptomatic for ≤ 4 years. In all 4 patients there has been recurrence of hypoglycemia over a 4–6-year period, and in each patient, recurrent disease was found in the liver. In two of these patients the liver metastasis was manifested only by very small superficial lesions found on the surface of the liver.

Prolonged Survival after Diagnosis of Liver Metastasis

Three patients have survived with metastatic disease to the liver for 16–30 years (Patients 1, 2, and 3), whereas hypoglycemia was controlled by diazoxide. Their prolonged survival seems to relate more to the biology of the disease than to any individual modality of treatment. In two of these patients, mild diabetes ensued after prolonged diazoxide therapy.

AFP–Producing Insulinoma

Patient 6 presented with a large liver metastasis. She had elevated AFP levels, commonly seen in hepatocellular carcinoma (HCC).⁹ Her symptoms were controlled in the short term by percutaneous radiofrequency ablation.

Discussion

Malignant or metastatic insulinoma is a rare condition.³ Patients with malignant insulinoma present with two fundamental challenges to the managing clinician. The first is that the tumor is, by definition, metastatic. The second is the unregulated secretion of insulin and proinsulin-related products that leads to severe hypoglycemia.⁴ In contrast to other islet cell tumors such as gastrinoma (Zollinger-Ellison syndrome) and vasoaltive intestinal peptidema (VIPoma), most insulinomas are believed to be benign.³ Only 5–12% of reported cases of insulinoma are malig-nant.^3,4,6

Most patients with malignant insulinoma have lymph node or liver metastasis^2,6 and only rarely other sites such as bone involvement.¹⁰ In spite of therapies in these patients that have been used with some short-term benefits including surgery, chemotherapy, embolization, radiofrequency ablation, and somatostatin analogs (Table 2), the prognosis of these patients is relatively poor with a median survival period of approximately 2 years.^6,11 Twelve of the 22 patients that we have followed over the past 30 years fit this general pattern. They present with liver metastases and usually undergo one or more of the therapies mentioned with limited benefit.⁶ The 10 patients who form the basis of the current report are clearly different in their clinical behavior. They have had a prolonged survival from the time of diagnosis or a prolonged interval between the excision of the initial pancreatic tumor and appearance of hepatic metastasis.

Table 2. Type of Therapies Available for Metastatic Insulinoma.

Type of treatment	References	Remarks
Radical surgery	Sarmiento et al., 20022; and Carty et al., 199230	Reserved for highly selected patients
Embolization	Moscetti et al., 2000,17; Winkelbauer et al., 199528; and Brown et al., 199929	Repeated procedures, when possible, may control symptoms
Chemotherapy	Moscetti et al., 200017; Sata et al., 1995,18; Schein, 197331; and Moertel et al. 198032	Toxic and low efficacy
Radio-ablation	Scott et al., 200219; and Tran et al., 200433	New promising approach to a selected group of patients
Somatostatin	Longnecker, 198826; Maton et al., 198927; Alberts and Falkson, 198834; Lawrence et al., 200135; and Gorden et al., 198936	There is little evidence for significant clinical benefit in most patients, and in some may result in a paradoxical increase in hypoglycemic severity
Conservative (e.g., diazoxide, glucagon)	Gill et al., 199721; D'Arcangues et al., 198437; and Samaan et al., 199038

The first challenge in treating these patients is to identify patients at risk for the more aggressive forms of the disease. To our knowledge, there currently are no histologic criteria that define malignancy other than the presence of disease at a metastatic site. We reviewed several features of the more aggressive patients in our previous published cohort⁶ and compared these with the current cohort of 10 patients to see if we could identify distinguishing characteristics.

In a review of the histology of the tumors, all of the primary and metastatic sites from both groups of patients were neuroendocrine tumors.⁶ There were no distinguishing morphologic features of the pancreatic tumor that predicted a subsequent metastasis or a lymph node metastasis. All patients had the characteristic inappropriate elevation of insulin and proinsulin levels at the time of diagnosis,⁴ but the more aggressive and less aggressive groups could not be distinguished nor could either be distinguished from the more common benign insulinoma. Although metastasis to the liver is usually but not always associated with poor prognosis,⁶ we as well as others¹² report that regional lymph node involvement does not always lead to a poor prognosis.

One patient had a large single liver metastases and elevated AFP levels. This is typical of HCC with noninsulinoma hypoglycemia,⁹ but is occasionally observed in patients with malignant insulinomas.^13,14 Yet, in most patients with metastatic insulinoma, we did not observe similar elevations of AFP, thus the predicative value of AFP level is low. Elevations of human chorionic gonadotropin or its α or β subunits sometimes occur but have not proved to be a consistent indication of malignancy.¹⁵

Furthermore, we as well as others^3,16–19 have identified a unique subset of patients who have a prolonged interval between primary tumor removal and evidence of metastatic disease. The suggestion for physicians is that currently there are no predictive factors to determine patients at risk for subsequent metastatic disease and there are no predicative factors to suggest how aggressive the disease may be. Conversely, only a few patients (approximately 2%) diagnosed with benign insulinoma will later present with metastatic disease.

It is clear that when all patients with malignant insulinoma are considered, the initial surgery for tumor removal or diagnosis is the most important factor in their management.⁶ After this, the biologic behavior of the tumor is the major determinant of long-term survival. All other modalities of therapy are, therefore, palliative and usually of short-term value. Diazoxide therapy for control of hypoglycemia has had the greatest long-term benefit.²⁰ Some patients have gastrointestinal intolerance to the drug and in very high doses it may produce anorexia.²¹ We have found that a small initial dose with an increase of ≤ 300–400 mg per day over 3–4 weeks is the most effective way to initiate and maintain therapy. All the other forms of therapy shown in Table 2 have either had no benefit or relatively short-term benefit and most, such as chemotherapy regimens, are toxic and of little benefit.^1,11,22–25 Somatostatin and its analogs are usually not helpful in malignant insulinoma and may make the situation worse by suppressing glucagon and growth hormone.^26,27 Of all the approaches available, embolization (Patient 1) may have the greatest benefit next to diazoxide. ^{17,23,25,28,29}

In the current study, we presented a subset of patients with malignant insulinoma who have had prolonged survival. Although malignant insulinoma represents only approximately 10% of patients with insulinoma,³ this unusual subset of patients may account for approximately 30% of patients with malignant insulinoma. Aggressive secondary therapies such as chemoembolization or radiofrequency ablation should only be used to control hypoglycemia. Because of low efficacy or toxicity, radical debulking surgery, chemotherapy, and somatostatin analogs should only be used in highly selected cases. Clearly, better molecular diagnostic techniques that will enable us to predict the biologic behavior of these tumors and the advancement of therapeutic approaches to treat malignant insulinoma are worthy goals for further investigation.