Abstract
Background/Aim: Pancreatic neuroendocrine tumors (PNETs) are pancreatic neoplasms with neuroendocrine features, divided into functioning and non-functioning. The non-functioning PNETs are the largest group, and their morbidity is the result of their potential to invade surrounding tissues and metastasize. The functioning PNETs produce hormonal symptoms due to over-secretion of specific hormones. They constitute 1% to 2% of all pancreatic tumors. The use of novel imaging methods has rendered their detection more frequent. Insulinoma, the most common functioning PNET, comprises 35-40% of all functioning PNETs. Its clinical presentation is due to hyperinsulinemia and the subsequent hypoglycemia. Glucagonoma accounts for 5% of all PNETs and is the fourth most frequent functioning PNET, following insulinoma, gastrinoma, and vipoma. Its symptoms are due to the massive secretion of glucagon and ensuing hyperglycemia. The co-existence of two PNETs is a very rare entity. This report aimed to describe cases of concomitant insulinomas and glucagonomas. Materials and Methods: A review of the literature was performed using the PubMed database and Cochrane library aiming to identify reported cases of concomitant pancreatic insulinoma and glucagonoma. Specifically, the research was conducted using the keywords, separately and in various combination, including insulinoma, glucagonoma, cystic, pancreatic neuroendocrine tumors and hypoglycemia. Only publications in English were included in the present study. Results: A total of 8 cases of concomitant pancreatic insulinoma and glucagonoma were identified, corresponding to the period 1992-2021. Conclusion: Concomitant insulinoma and glucagonoma are rare and challenging. A multidisciplinary approach is necessary for diagnosis, prognosis, and therapy.
Neuroendocrine tumors (NETs) are neoplasms, which demonstrate neuroendocrine features, including the presence of secretory vesicles, production of neuropeptides and absence of neural structures (1-3). The pancreatic neuroendocrine tumors (PNETs) are a common group of NETS arising from the islet cells of the pancreas and can be divided into functioning and non-functioning subtypes (4). The non-functioning PNETs are the largest group, and their morbidity is attributed to their potential to invade surrounding tissues and metastasize to distant sites. On the contrary, the functioning PNETs produce symptoms in accordance with their respective hormone-secreting profile (1-3). In recent years, the overall incidence of PNETS has been steadily increasing (5). In the USA, the annual incidence is estimated at 1.0 per 100.000, constituting 1% to 2% of all pancreatic tumors (6). Nowadays, it is widely accepted that the extensive use of cross-sectional imaging in the evaluation of a variety of clinical conditions has rendered their incidental detection more frequent, with an increased number of early-stage PNET diagnoses over the last twenty years (7).
Insulinoma is considered the most common functioning PNET. Approximately 35-40% of all functioning PNET cases are attributed to insulinomas while its clinical presentation is the result of the established hyperinsulinemia and the ensuing hypoglycemia (8, 9). On the contrary, glucagonoma accounts for 5% of all PNETs and is the fourth most frequent functioning PNET, following insulinoma, gastrinoma and vipoma (10). Its clinical features are due to the massive secretion of glucagon and subsequent hyperglycemia (9). Insulinomas and glucagonomas are considered distinct entities due to their unique hormonal and clinical characteristics but in rare cases, these neoplasms can develop concomitantly in the same patient leading to more challenging clinical implications.
In this article, we conduct a review of the literature with the purpose of retrieving all cases of concomitant insulinomas and glucagonomas corresponding to the time span between 1992 and 2023.
Materials and Methods
A review of the literature was performed using the PubMed database and Cochrane library to identify publications related to concomitant pancreatic insulinoma and glucagonoma. Specifically, the search was conducted through the use of appropriate keywords, separately and in various combinations, including “insulinoma”, “glucagonoma”, “cystic”, “pancreatic neuroendocrine tumors” and “hypoglycemia”. In addition, a reverse snowballing strategy was employed to ensure that no eligible article will be missed. Furthermore, title and abstract screening identified 17 articles. No duplicates or overlapping articles were found during the overlap check process. All 17 reports underwent further screening and 9 were excluded for various reasons. Some of them were only abstracts, whereas others were not completely relevant to the topic. Only publications in English were included in the present study. A total of 8 full-text articles were assessed for eligibility. None of them was excluded. The inclusion process is shown in Figure 1.
PRISMA flow diagram for the current study.
Results
There are very few cases in current literature of simultaneous existence of insulinoma and glucagonoma (Table I).
Reported cases of concomitant insulinoma and glucagonoma.
In 1992, Yahigashi et al. reported a case of a 28-year-old woman who suffered from tremor, diplopia, and concurrent episodes of unconsciousness (11). The laboratory findings showed low levels of fasting glucose (less than 70 mg/kg) and high levels of insulin. The abdominal Computed Tomography (CT) revealed a cystic pancreatic lesion. Following a caudal pancreatectomy multiple lesions were identified. The surgical specimen was examined histopathologically leading to a diagnosis of both insulinoma and glucagonoma. The clinical outcome was excellent.
In 2009, Nisciuchi et al. described a case of a 58-year-old man with MEN1 syndrome and co-existent insulinomas and glucagonomas (12). The patient presented with glycopenic symptoms, low glucose plasma levels and elevated insulin levels. An abdominal CT depicted two lesions at the body and tail of pancreas. He underwent distal pancreatectomy and enucleation of the tumors in the body. The pathologist found lesions compatible to insulinoma and glucagonoma. Ever since, he is healthy and asymptomatic.
Three years later, Varsavksy et al. referred to a 25-year-old female, who suffered from MEN1A syndrome (13). Except for the other symptoms of the syndrome, she complained about glycopenic episodes. The laboratory examination demonstrated high C-peptide levels and low glucose levels. An abdominal Magnetic Resonance Imaging (MRI) showed pancreatic lesions. A Whipple procedure was performed, which proved the existence of pancreatic insulinoma, glucagonoma and somatostatinoma.
The following year, Yamashita et al. reported a case of a 70-year-old man with disturbance of consciousness (14). He had high levels of insulin, C-peptide, and fasting glucose. Abdominal CT and ultrasonography (US) revealed a tumor of 1 cm in the tail of pancreas. A distal pancreatectomy was performed and the immunohistochemical staining showed co-existence of insulinoma and glucagonoma. His post-operative course was uneventful, and the patient remains asymptomatic ever since.
In 2015, Chen et al. described a case of a 51-year-old woman suffering from MEN1 syndrome (15). She complained about hypoglycemic episodes and epigastric pain. Her laboratory examination revealed increased levels of insulin, C-peptide, and low levels of insulin. The abdominal CT demonstrated a pancreatic tumor in the tail. The patient underwent surgery and the histologic analysis showed multiple glucagon tumors and a single lesion, larger than the glucagonomas, corresponding to an insulin tumor.
In 2020, Erichsen et al. reported a case of a 14-year-old patient with MEN1 syndrome who presented with a one-year-long history of unrecognized hypoglycemic symptoms. After multiple imaging tests including MRIs and Positron Emission Tomographies - Computed Tomographies (PET-CTs) and a total of four surgeries the final diagnosis was occult insulinoma, glucagonoma and pancreatic endocrine pseudotumor. The first PET-CT indicated a small focal process in the head of the pancreas, which was surgically resected. Immunohistochemical staining of the lesion settled the diagnosis of PNET. Nevertheless, during the first postoperative days, hypoglycemia recurred. Repeat PET-CT scan failed to identify any remaining pathological pancreatic lesion. A subsequent PET-CT showed two small foci in the uncinate process of the pancreas leading to a second surgery and to the resection of a part of the pancreatic head and a modified Roux-en-Y procedure. The histological staining showed glucagonoma. Even after the second surgery, the hypoglycemia recurred after 7 days. Again, the PET-CT that followed showed no evidence of pancreatic tumor. The patient was then administered to a specialized center to undergo a 111In-exendin-single-photon emission computerized tomography (SPECT) scan during iv glucose delivering, which identified increased uptake of 111In-exendin in the remaining head of the pancreas close to the common bile duct. After a third surgical operation with a modified Whipple’s procedure and a histological finding of PNET, the patient remained asymptomatic for two months. At this time both PET-CT and MRI of the pancreas showed a process in the tail of the pancreas, which was finally resected. The immunohistochemical staining showed insulinoma and the patient is finally free from hypoglycemic episodes (16).
In 2020, Mantas et al. presented a case of a 24-year-old patient with a solitary pancreatic cystic lesion, in which co-existed both an insulinoma and a glucagonoma. The patient whose family history was unremarkable, presented with symptoms of hypoglycemia. The first approach to this patient was a prolonged fasting test which was indicative of insulinoma. A CT scan showed a 4 cm cystic lesion of the pancreatic tail. In the light of these findings, an endoscopic US (EUS) was performed, and the cytological result of the biopsy taken was compatible with PNET. Surgical treatment was decided, and the patient underwent distal pancreatectomy. Histology revealed the co-existence of an insulinoma and a glucagonoma, and gene analysis showed no MEN1 mutations (17).
In 2021, Ozbas et al. presented the case of a 23-year-old male patient with recurrent hypoglycemic symptoms. The patient’s laboratory examinations revealed primary hyperparathyroidism, hyperprolactinemia and hyperinsulinism. An abdominal CT detected multiple hypodense mass lesions in the tail and body of the pancreas. Due to the clinical symptomatology, family history, and he frameshift mutation in the MEN1 gene due to pathogenic deletion, the patient was diagnosed with MEN-1 syndrome. The patient underwent parathyroid, pituitary, and finally pancreatic surgery, which confirmed the co-existence of adenoma in the left inferior parathyroid gland, pituitary adenoma, as well as two PNETs with different characteristics. Nine years post-operatively, the patient re-presented with nausea, vomiting, abdominal pain and hypercalcemia. The performed PET-CT revealed gallium-68 DOTA-TATE involvement in the pancreatic tail, in the uncinate process of the pancreas, as well as proximally to the pancreatic neck. A CT-guided biopsy of the pancreatic mass lesion confirmed the existence of PNET and the patient, who had refused a surgical excision of the mass, was put on monthly lanreotide therapy (18).
Discussion
We identified 8 reported cases of concomitant insulinoma and a glucagonoma in the literature. Four patients were female and four males. Their age varied from 14 to 70 years, with a mean age of 36.6 years (11-18). Most concomitant insulinomas and glucagonomas arose in the tail of the pancreas (4 cases) (11, 14, 15, 17); however other locations such as pancreatic head and body (12, 13), pancreatic head and tail (16) or pancreatic body and tail (18) were also reported. The co-existence of these tumors presents as a single or multiple lesions. In particular, there were three patients with a single lesion (14, 15, 17), two patients with three distinct lesions (12, 18), one patient with five lesions (16), one patient with six lesions (11) and one patient with nine lesions (13). Maybe an association between the sex and the number of the lesions. The majority (two out of three) of patients with single lesion were males (14, 15, 17), while the majority (3 three of five) of patients with multiple lesions were female (11-13, 16, 18). As the reported cases are only eight, we cannot draw safe conclusions. A wide range of lesion sizes has been reported, as the diameter was ranging from 0.2 mm to 4 cm (11-18).
Regarding the symptoms, in all cases, the glycopenia was dominant (11-18). The glycopenic symptoms derive from insulinoma. The b-cells of the tumor secrete insulin and cause the Whipple’s triad. Their clinical manifestation includes blurred vision, palpitation, sweating, weakness, tremor, and confusion (9). In glucagonoma, the excessive secretion of glucagon through the a-islet pancreatic cells causes diabetes mellitus, weight loss and necrolytic migratory erythema (NME) (10). It usually involves the gluteal region and migrates to the distal extremities. It is also associated with cheilitis, atrophic glossitis, anemia, and thromboembolism (19). Only the patient described by Yamashita et al. suffered from diabetes mellitus (14). However, the statement that diabetes mellitus developed in this patient as a result of glucagonoma should be approached with appropriate skepticism as the causation between the two entities cannot be verified.
Regarding the laboratory findings, the C-peptide, proinsulin, and insulin levels are high in insulinoma, whereas fasting blood glucose is low (20). In glucagonoma, a prerequisite for diagnosis is confirmation of a pancreatic neoplasm, along with glucagon serum levels from 500 to 1,000 pg/ml (19).
The imaging methods used for the detection of these neoplasms are mainly CT, MRI, US, and octreotide scintigraphy (21-23). Unfortunately, the ability of CT and MRI to detect small lesions is limited (21, 22). Insulinomas are generally small lesions, less than 2 cm, well-circumscribed with equal distribution through the pancreas (23). The EUS is regarded as the best method to detect insulinomas (24). On the contrary, glucagonomas are bigger in size (2 to 25 cm) and tend to metastasize in the liver (23). Their size renders their detection easier. Confirmation of diagnosis requires the examination of the specimen by a pathologist. The insulinomas are characterized by stromal deposits of islet amyloid peptide and amylin (25). The glucagonomas contain glucagon-producing neoplastic cells (26). In all cases, the diagnosis of glucagonoma was conducted post-operatively by the pathologist (11-18).
The treatment of insulinoma is surgical resection (21, 22). Medical management comprises somatostatin analogues, diaxozide or mTOR inhibitors in unresectable or metastatic insulinomas (27). Due to higher rates of metastasis in glucagonomas, combination therapy of surgery and medical treatment is usually necessary (28). All cases reported in this review underwent surgery with either pancreatectomy or enucleation of the lesions (11-18).
It is important to mention the correlation of MEN1 syndrome with PNETs (9). In this syndrome, endocrine tumors appear in the anterior pituitary, parathyroid glands, and islets of pancreas (29). The non-functioning type of PNET is the most frequently associated with MEN1 syndrome. However, there are many cases of insulinoma and glucagonoma, in which MEN1 syndrome coexists (30). Four out of seven cases in this review are related to MEN1 syndrome (12, 13, 15, 16, 18).
Lastly, the presence of a cystic lesion dramatically increases the diagnostic challenges. Cystic PNETs account for 13%-17% of all PNETs (31) and 9-10% of resected cystic tumors (32). Their origin is controversial. They derive either from necrosis of a solid PNET or are distinct entities (31). The differential diagnosis includes benign and malignant lesions, such as cystadenomas, intraductal papillary mucinous neoplasms, ductal carcinoma, mucinous cystic neoplasms, and acinar cell carcinoma (33).
Conclusion
In conclusion, this article summarizes clinical cases of the rare co-existence of two functioning PNETs. Both diagnosis and treatment of this entity is a challenge in the daily clinical practice. Thus, a multidisciplinary approach towards this disorder is necessary in order to achieve the best clinical outcome regarding diagnosis, prognosis and therapy.
Footnotes
Authors’ Contributions
CD, DD, and NG designed the study. CD, DD, AG, and NG wrote the article. CD, AG, GK (Georgios Kyriakos), PF, AP, and NG collected the data. CD, DD, EAA, GK (Gregory Kouraklis), ED, GM, and KK offered scientific advice. IP and MM revised the manuscript. NG supervised and critically revised the manuscript and was the supervisor.
Conflicts of Interest
All the Authors declare that there are no conflicts of interest in relation to this study.
- Received June 5, 2023.
- Revision received August 3, 2023.
- Accepted August 7, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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