Insulinomas attract clinical attention out of proportion to their low incidence because of their nonspecific and sometimes unusual presenting symptoms and their high cure rate with surgery. The association between insulinoma and hypoglycemia was first recognized in 1927, when extracts from a metastatic insulinoma were injected into a rabbit to produce effects of hypoglycemia.9
Two years later, Roscoe Graham performed the first curative operation for a benign insulinoma in Toronto, Canada.10
Since that time there have been many reports of successful management of insulinoma in both the medical and surgical literature. Most of these reports are based on small numbers of patients or are multi-institutional studies.11
Recommendations regarding investigation of patients with insulinoma before surgical resection, surgical technique and prognostic factors are not clearly defined.12–14
A delay in diagnosis is a common feature of patients with insulinomas. The median duration of symptoms before diagnoses in 224 patients treated at the Mayo Clinic over 60 years was 18 months,1
which is equivalent to our series. Hypoglycaemic events can be nonspecific and patients often self-treat with frequent meals to avoid symptoms. This commonly leads to weight gain, as noted in 44% of our patients. In fact 1 patient, who had symptoms for 3 years before diagnosis, weighed 294 kg (648 pounds) at the time of surgery. The most common presenting symptoms in our series were confusion, visual disturbances, and diaphoresis. Other large series report confusion and behavioral changes as the most common presenting symptoms.2, 15
Seizures were presenting symptoms in 10 patients (16%), 4 of whom had extensive neurologic work-up for presumed primary seizure disorders. Overall, the duration of symptoms and the type of symptoms did not correlate with disease severity and longterm DFS. Biologically more aggressive tumors do not seem to be clinically detected at earlier time points or produce distinct symptoms.
The need for preoperative localization in patients with biochemically proven insulinoma is debated.16–18
Many authors, quoting low preoperative detection rates compared with intraoperative palpation and ultrasound, advocate minimization of preoperative imaging. The rate of intraoperative detection, however, varies between studies, ranging from 83% to 98%.15,16,19,20
In our series, the sensitivity of IOUS and palpation was 92%. This compares very favorably to the 29% sensitivity of preoperative noninvasive imaging between 1983 and 1993. However, since then the sensitivity of noninvasive imaging has improved markedly and was 80% between 1994 and 2007. This included the identification of 4 nonpalpable lesions, including 1 that could not be identified with IOUS. One should also be mindful that most of the recommendations regarding the need for preoperative localization were before the widespread use of EUS. There are several reports quoting sensitivities of 86% to 94% for EUS detection of neuroendocrine neoplasms.21–23
When combined with noninvasive imaging, the sensitivity approaches 100%.21
This is supported by our study in which EUS alone had a sensitivity of 92% and when combined with CT and MRI, increased to 96%. Between 1994 and 2007 our overall preoperative detection rate, utilizing noninvasive and selected invasive modalities, particularly EUS, was 98% (40 of 41). The need for THPVS and calcium stimulation seems unnecessary, since the introduction of EUS. Although there is no doubt that this form of localization is highly accurate, its major role would seem to be when other imaging has failed.24–26
Given that intraoperative palpation and ultrasound does not guarantee tumor detection, we feel strongly that optimized preoperative localization is essential in planning and minimizing unnecessary surgery.
A major dilemma arises at the time of surgery when tumor localization fails. In some series up to 25% of insulinomas go undetected.27,28
In this series, 3 patients (5%) had failed blind distal pancreatic resections and were eventually found to have tumors located in the uncinate process or deep within the pancreatic head. Of interest, 8 of 10 (80%) nonpalpable insulinomas in our study were located in the pancreatic head. There are reports that up to 67% of pancreatic head insulinomas are nonpalpable.20
In an international multicenter review of 396 resected insulinomas, there were 53 reoperations, with 46 (87%) of them being for pancreatic head lesions.11
Based on these reports and our own experience, historical arguments for blind distal pancreatic resection should be abolished.29
In fact, more concerted efforts should be placed on fully displaying and imaging the pancreatic head and uncinate in situations when initial tumor localization fails. If there is any diagnostic doubt, reassessment, including THPVS and calcium stimulation, is indicated.24–26
The appropriate surgical policy for insulinomas is unclear. A pancreatic sparing approach is however advocated by most authors.1,11,30
Enucleation (34%) and distal pancreatectomy (40%) were the preferred surgical techniques in our series.
Compared with other large reviews, enucleation was performed less commonly in our series.1,11
In fact, in the review by Rothmund et al, enucleation was performed in 208 of 383 (54%) cases, and pancreaticoduodenal resection was performed in only 19 (5%).11
Comparatively, in our series pancreaticoduodenal resection was performed in 10 of 61 cases (16%). These differences may reflect our greater reluctance to perform enucleation, with its risk of pancreatic duct injury, when lesions are deep within the pancreatic head. Pancreaticoduodenal resection in our institution is safe, with acceptable morbidity and very low mortality.31
The overall median hospital stay of our patients was 7 days and the pancreatic fistula rate 18%, with most fistulas having minimal impact on postoperative stay.
Our study shows that enucleation can be performed with acceptable morbidity in selected patients with insulinoma, and long-term DFS can be achieved even in the presence of positive resection margins. We limited enulceation to superficially located insulinomas less than 25 mm (median of 15 mm) in maximum diameter. Two cases were complemented with a Roux-en Y onlay to the pancreatic defect, when pancreatic duct injury was suspected. Nonetheless, pancreatic fistulas were detected in 5 of 21 (24%) patients after enucleation, 4 of which had minimal clinical impact (Grade A). This compares favorably to other series that report pancreatic fistula rates as high as 57% after enucleation3,32
Of note, 7 of 21 (33%) patients treated by enucleation had positive margins on histology. None had recurrence at the site of enucleation on long-term follow-up. One may infer that “enucleation” implies positive margins. However, the aim of enucleation is to “minimize” pancreatic parenchymal excision by using the tumor pseudo-capsule to guide the limits of resection, including excision of the layer of compressed tissue that surrounds the specimen. To our knowledge, no earlier reports have examined the implication of a positive margin after enucleation of insulinomas.
The best surgical approach for patients with insulinomas in the setting of MEN-1 is controversial. Because these patients are more likely to have multiple and malignant neoplasms, some advocate an 85% subtotal pancreatectomy to the level of the portal vein along with enucleation of lesions from the pancreatic head.33,34
The recurrence rate at 20 years after resection in MEN-1 patients is quoted as 21%.33
However, whether more extensive pancreatic resection has an impact on the OS of these patients is unknown. Not all patients with MEN-1 have aggressive disease, and such an approach cannot be definitively advocated unless one can identify the subset of patients with specific MEN-1 mutations or pathologic features that are most likely to benefit from radical surgery. Subtotal pancreatectomy and enucleation of a neoplasm in the pancreatic head was performed as initial surgery in 1 patient in our series with multiple lesions. In another MEN-1 patient with multiple lesions, development of new metachronous islet-cell tumors required reoperation 4 years after initial enucleations. Given that redo pancreatic surgery in large volume centers has low morbidity,35
a reoperation policy for patients with MEN-1 and recurrent insulinoma remains an alternative option to initial subtotal pancreatectomy.
The pathologic features of insulinomas observed in our series were consistent with other large reports and collective reviews.1,15,16
In patients with sporadic insulinomas, multiple tumors were noted in only 4% of cases, and the rate of malignancy was only 6%. The overall median tumor size was 15 mm. We found no association between size, malignancy, and symptoms. This contrasts with a multi-institutional review of 62 patients with malignant insulinomas, which showed a relationship between tumor size and malignancy.36
The median size of malignant tumors in that report was 47 (10 –90) mm, and was greater than the median size of 25 (14 –38) mm of malignant insulinomas in our study. The actual definition of pancreatic neuroendocrine malignancy per se is controversial. To be classified as malignant by the WHO classification, a neuroendocrine neoplasm must show either local invasion into surrounding soft tissue or organs, or display lymph node or distal metastases.8
There are growing reports that vascular invasion, perineural invasion, mitotic rate, proliferation, necrosis, and the presence of a pancreatic ductal phenotype are all features of more aggressive biologic behaviors and should be considered in the classification or definition of malignacy.37,38
Tumor lymphovascular invasion was noted in 10% of patients in our series and proved to be an important prognostic factor, but given the low number of recurrences (5 cases), this finding may not be conclusive. Whether these patients would benefit from a more extensive pancreatic resection and whether such tumor features could be detected by tumor frozen section to guide surgery is unknown.
The 5, 10, and 20-year DSS of patients with insulinoma in this study was 100%, 100%, and 93% and is consistent with other larger series.13,15,39
This was significantly better than the overall survival, indicating that most patients with resected insulinomas eventually die of other causes. The 5-year DFS in this series was 90%, with no further recurrences thereafter. Danforth et al reported a 63% recurrence rate in 62 patients with malignant insulinomas at a median interval to recurrence of 2.8 years.36
Based on this study and our series, one can infer that most recurrences after resection of insulinomas occur within 5 years. On univariate analysis, only the presence of lymph node metastases, tumor lymphovascular invasion, and MEN-1 affected DFS and on multivariate analysis, the only predictor was lymphovascular invasion. These patients may be the ones to potentially benefit most from novel adjuvant therapies.
In summary, this 25-year single-institution series highlights the contemporary management of insulinomas, allowing formulation of a useful treatment algorithm. It is clear that a delay in diagnosis continues to be a feature of insulinomas, although this does not seem to have major prognostic implications. Diagnosis must be confirmed with appropriate laboratory testing in the setting of hypoglycemic symptoms. Preoperative localization is essential to minimize unsuccessful blind surgical resection, and currently arterial enhanced high-resolution CT or MRI scanning is the initial imaging of choice. If these fail to identify the lesion, EUS will achieve detection of tumors in the majority of cases. THPVS should be reserved for exceptional cases that are not identified by less-invasive imaging. At the time of surgery, most lesions are detectable by a combination of palpation and IOUS. Those that remain occult are most likely to be located in the pancreatic head. In patients without MEN-1, enucleation, or a conservative pancreatic resection is the preferred surgical option. A positive margin after enucleation is common but seems not to increase local recurrence. Although most insulinomas are benign and long-term survival is expected after surgery, a few do recur. Lymphovascular invasion is an independent predictor of recurrence and may potentially guide the need for adjuvant therapies or perhaps more extensive resection if discovered by intraoperative frozen section.