Primary Functioning Neuroendocrine Tumor of the Appendix with Hypoglycemia Syndrome: A Case Report and Review of Neuroendocrine Tumors


Peter F Layman, DO1; Deborah Davis-Merritt, MD1; Phillip Neff, MD1,2

Perm J 2020;24:19.142 [Full Citation]
E-pub: 03/13/2020


Introduction: Primary neuroendocrine tumors (NETs) of the appendix are uncommon, but when present are usually not hyperfunctioning. This case represents an extraordinarily rare primary hyperfunctioning NET of the appendix with a clinical presentation of symptomatic hypoglycemia in an otherwise healthy man.
Case Presentation: A previously healthy 34-year-old man was found to be symptomatically hypoglycemic in early 2018. After the workup, the apparent explanation was a tumor in his midappendix, for which he was referred to our surgical oncology service for resection. The patient’s clinical course is described in detail, including imaging, as well as surgical and pathologic descriptions of the appendiceal NET.
Discussion: A literature review demonstrates no other case series or reports of a primary hyperfunctioning NET of the appendix presenting with hypoglycemic crisis. The symptoms of tumor-induced hypoglycemia more typically arise with islet cell tumors, such as pancreatic NETs or insulinomas. We believe this case represents a nonislet cell tumor-induced hypoglycemia. This patient’s elevated serum proinsulin level preoperatively implies secretion of proinsulin by the tumor. However, tumor-induced hypoglycemia caused by proinsulin has been described previously only in pancreatic tumors. This unique case adds knowledge to the possible glycemic endocrine effects of nonpancreatic NETs, specifically those that arise primarily in the appendix.


Tumors of the appendix are a well-known phenomenon but are overall an uncommon disease. One study reports an incidence rate of 0.12 cases per 1,000,000 people per year.1 Neuroendocrine tumors (NETs), classically described as “carcinoid” tumors, represent up to 80% of all appendiceal neoplasms, but there are other histologic subtypes that make up a small minority.2 Usually, NETs of the appendix are found serendipitously on pathologic examination and often do not require further intervention.3 Symptoms associated with these tumors are typically related to obstruction, clinically consistent with appendicitis. Systemic symptoms of carcinoid syndrome have been described with an appendiceal primary tumor, but this constellation is rare and does not historically include symptoms of hypoglycemia crisis. To our knowledge, there are no reports of primary appendiceal NETs that produce hypoglycemic symptoms, typically described with insulinomas. This case provides detailed reports of the clinical course of our patient for whom a pathophysiologic explanation for hypoglycemia was his appendiceal NET. This analysis provides what appears to be one possible mechanism for tumor-induced hypoglycemia, the increased secretion of proinsulin. This is an addition to our fund of knowledge of the endocrine effects of NETs and illustrates one possible mechanism for tumor-induced hypoglycemia, secretion of proinsulin.


A previously healthy 34-year-old male teacher presented with what probably was symptomatic hypoglycemia in early 2018. He arrived at an urgent care facility with neurologic complaints of left-sided facial and extremity tremor. His initial serum glucose level was 38 mg/dL (reference range = 60-140 mg/dL). His care was managed by the endocrinology service, and his initial symptoms improved with intravenous (IV) administration of 50% dextrose with continued infusion. He had no history of diabetes mellitus, alcohol abuse, or smoking, and he denied taking any glucose-lowering medications. The physical examination revealed no clinically significant findings.

Results of further laboratory workup showed no evidence of exogenous insulin or sulfonylurea, and his serum insulin and C-peptide levels were normal, but his proinsulin level was greatly elevated (131.5 pmol/L; reference range ≤ 18 pmol/L). Results of a computed tomography (CT) scan of the chest, abdomen, and pelvis revealed a 1.2-cm mass of the midappendix (Figure 1) and no masses of the pancreas or duodenum. Treatment goals were curative resection for relief of symptoms, and he was referred to our surgical oncology service the following month.

Presenting Concerns

This patient’s presenting symptoms were consistent with Whipple triad: Fasting hypoglycemia, symptoms occurring at the time of measured low serum glucose levels, and immediate relief of symptoms after the IV administration of glucose. The primary concern would be to rule out any cause of iatrogenic hypoglycemia, such as surreptitious use of insulin or sulfonylurea. With an iatrogenic cause already ruled out, a workup for tumor-induced hypoglycemia proceeded. The most common cause of this presentation is an insulinoma. Insulinomas are NETs derived of pancreatic beta cells and are found almost exclusively in the pancreas and duodenum.4 The results of the patient’s laboratory evaluation were inconsistent with an insulinoma, with a normal C-peptide level indicating that the patient was not producing excess endogenous insulin. However, there was an elevated proinsulin level, which can occur with proinsulinomas, which historically reside exclusively in the pancreas.5 

A gallium dotatate Ga 68-enhanced positron emission tomography/CT scan, also known as a gallium scan, was performed, and the results confirmed an appendiceal tumor with metabolic activity and no other sign of disease outside the appendiceal mass (Figures 2 and 3). With the objective findings consisting of only a mass on the appendix that was seen on the abdominal CT scan, and the gallium scan confirming this mass as suspicious with no activity in the pancreas, a biopsy of the pancreas was performed, although pancreas vein sampling would have been preferable to rule out islet cell tumor hypoglycemia. When the pancreas biopsy specimen was found to be normal, it was decided to intervene on the appendiceal mass as the most likely cause of his hypoglycemia.

Therapeutic Intervention and Treatment

Initial treatment of this patient consisted of IV administration of 50% dextrose with continued infusion while he remained an inpatient for his diagnostic workup. Once discharged, he was maintained on a regimen of diazoxide (Proglycem), 50 mg/mL oral suspension taken as 1.2 mL every 12 hours. He was also given rescue glucagon 1-mg intramuscular injections for treatment of hypoglycemic crisis. His response to glucagon was not measured. He was maintained on this treatment until he was seen by our surgical oncology service the following month and was evaluated for surgical resection. Given the small size and the location of the tumor, he was advised that a laparoscopic appendectomy was likely sufficient but that an ileocecectomy might be required depending on operative findings.

At the time of laparoscopic exploration, a clear mass was seen in the midappendix more than 2 cm away from the appendiceal base, with no involvement of adjacent structures or evidence of metastatic disease or other masses. The appendix was removed, and a single line of surgical staples (Endo GIA stapler, Covidien Medtronic, North Haven, CT) was applied across the base of the appendix and another across the appendiceal mesentery. The specimen was evaluated intraoperatively by the surgical team and the pathologist; with clear margins, no involvement of the base, and a tumor diameter of less than 2 cm, the decision was made to conclude the operation.

The patient was observed overnight in the hospital. Serum glucose levels were checked every 6 hours, and he remained normoglycemic with no intervention. He was discharged on postoperative day 1. Pathologic evaluation confirmed a well-differentiated NET with negative margins (Figure 4). Microscopically, the tumor had a mitotic rate of less than 2 mitoses/mm2 and a Ki-67 labeling index of 1% (reference range < 3%). There was no lymphovascular or perineural invasion and no necrosis. The round, uniform cells arranged in clusters with a prominent rosette formation and “salt and pepper type” chromatin were characteristic of a NET (Figure 5).

Follow-up and Outcomes

One month after resection, the patient followed-up in our clinic. He had recovered well from surgery and had no further symptoms of hypoglycemia. His measured fasting blood glucose level was between 80 mg/dL and 90 mg/dL without any requirements for dextrose or intramuscular glucagon injections. Results of a repeated laboratory evaluation postoperatively showed the following normal values: Insulin, 2.9 µIU/mL (reference range = 2.0-19.6 µIU/mL); C-peptide, 0.7 ng/mL (reference range = 0.8-3.8 ng/mL); and proinsulin, below 4.0 pmol/L (reference range ≤ 18 pmol/L). Our plan for continued follow-up is to repeat the gallium dotatate scan in 6 months. Figure 6 shows a timeline of the case.



It is important to consider the definitions of tumors considered in this case because the topic of NETs and the specific terms have changed over time and are frequently confused. NETs are a heterogenous group of malignancies with varied histologic findings and nomenclature.6,7 The tumors are classified on the basis of both the “neuro” and “endocrine” histologic factors found in them. A consistent finding of dense core granules with a salt and pepper appearance that are similar to those found in serotonergic neurons makes up the descriptor of “neuro.” The “endocrine” refers to these core granules’ ability to secrete monoamines. Historically, these well-differentiated tumors were referred to as carcinoids, but this term led to errors in communication. In 2010, changes by the World Health Organization deemed that all tumors with histologic findings consistent with immunoexpression of neuroendocrine markers such as chromogranin A and synaptophysin in an organoid or neuroendocrine shape would be defined as neuroendocrine neoplasms or NET, scuttling the previous term carcinoid tumors.6,7 

NETs can occur in a variety of tissues, but those that occur in the gastroenteropancreatic system are the most common (62%-67%).8 These gastroenteropancreatic tumors are subdivided into 2 basic types: 1) those that occur in the pancreas, or pancreatic NETs; and 2) those occurring in the luminal gastrointestinal tract, or nonpancreatic NETs. Pancreatic NETs are tumors that are capable of producing systemic syndromes related to endocrine function of the tumor given its cell origins. These tumors are classically described as insulinomas, gastrinomas, pancreatic polypeptide-secreting tumors, VIPomas (secreting vasoactive intestinal polypeptide), glucagonomas, and somatostatinomas.6,9 Even rarer, however, are proinsulinomas, which are described later in this article.5 Nonpancreatic NETs such as those that occur in the stomach, small bowel, colon, appendix, and rectum can be hyperfunctioning, resulting in the carcinoid syndrome because of the hypersecretion of vasoactive amines and peptides from the tumor. The symptoms of this classic syndrome—watery diarrhea, flushing, bronchospasm, hypotension, and right-sided heart failure—do not include hypoglycemia.6

Tumor-induced hypoglycemia is a phenomenon that can be explained by 2 distinct pathophysiologic processes. The first and most common is the result of insulin secretion by tumors of pancreatic islet cell derivation (insulinomas), and referred to as islet cell tumor hypoglycemia. However, tumor-induced hypoglycemia can also develop in nonpancreatic tumors known as nonislet cell tumor hypoglycemia (NICTH). This case illustrates a previously undescribed phenomenon of NICTH derived from a primary appendiceal NET.

Ectopic insulin secretion from pancreatic beta cell tumors (insulinomas) is rare, with an incidence of 0.4/100,000 person years.6 This tumor is the most common functioning pancreatic NET. They are usually small and almost always located in the pancreas but have been known to reside in the duodenum or gastrohepatic ligament.7,4,10 Our patient’s presentation with symptomatic hypoglycemia that resolved with IV glucose administration ultimately spurred an investigation for a possible pancreatic NET; however, none could be seen on imaging studies. Given the rarity of other types of tumor-induced hypoglycemia, a pancreatic biopsy was performed that yielded normal tissue. With this in mind, other forms of tumor-induced hypoglycemia were considered.

A small number of nonislet cell tumors have been associated with ectopic insulin secretion.10 Among these are bronchial carcinoid tumors,11 squamous cell carcinoma of the cervix,12 neurofibrosarcoma,13 schwannoma,14 paraganglioma,15 small-cell carcinoma of the cervix,16 and gastrointestinal stromal tumors.17 Some of these reports do not entirely explain the pathophysiologic mechanism for hypoglycemia because a pancreatic insulinoma was not specifically excluded. However, case reports of paragangliomas and small-cell carcinomas of the cervix have shown that the nonislet cell tumors were the source of the hyperinsulinemia given the detection of proinsulin mRNA and insulin protein in the tumor cells.15,16 The common factor among most of these tumors is that they are derived from mesenchyme or epithelium. Reporting on the percentages of nonislet cell tumors associated with hypoglycemia, de Groot et al18 concluded that NICTH can arise in virtually every benign and malignant tumor but mainly occurs with solid tumors of mesenchymal or epithelial origin, with 41% and 43% of these respective tumor classes having associated hypoglycemia. Interestingly, in their review, only 1% of nonpancreatic NETs were found to be associated with hypoglycemia, and of these cases, none was of primary origin of the appendix.18

A PubMed literature review found few reports of nonpancreatic NETs with associated hypoglycemia. One recent publication did describe a NET of the kidney that produced ectopic insulin, requiring IV dextrose fluid resuscitation and curative resection.19 Another nonpancreatic NET found was of gastric origin that also required blood glucose intervention and resection.20 Curiously, these 2 tumors acted via different mechanisms in producing systemic hypoglycemia. The tumor found on the kidney produced ectopic insulin confirmed by elevated serum insulin and C-peptide levels.19 The gastric NET did not produce ectopic insulin, and the authors proposed that the tumor’s pathophysiologic mechanism of action was via insulinlike growth factor 2 (IGF-2).20 

The pathophysiology of NICTH can be explained by several mechanisms. The first and most coherent is ectopic production of insulin by the tumor itself. Although this is typically described in islet cell tumors, it can also occur in NICTH but, again, is extremely rare. The clinical picture of this constellation would consist of elevated C-peptide levels as well as elevated serum insulin levels. Because our patient did not fit this clinical picture, we will not elaborate on this mechanism. Another mechanism commonly described is tumor production of IGF-2. Produced in the liver, IGF-2 binds to the same high-affinity tyrosine kinase receptors on cells as insulin.21 When a tumor secretes IGF-2, which is sometimes referred to as “big IGF-2” prohormone, it inhibits the secretion of insulin and growth hormone. The IGF-2 molecules interact poorly with the tyrosine kinase receptors, and this leads to high levels of free IGF-2 molecules, which cause hypoglycemia by inhibiting hepatic glucose uptake and enhancing the disposal of glucose into muscle.22 Several tumors and tumor syndromes have been associated with excess IGF-2 secretion, such as Doege-Potter syndrome.23 These tumors are almost always epithelial in origin, and this mechanism has not been described in great detail with an associated NET. Other described mechanisms include tumor consumption of glucose, but this has been attributed to large NETs of the mesenchyme10 and would not fit logically with our case. Also described are a combination of cachexia and renal and hepatic dysfunction,24 which, again, our patient did not manifest.

In reflection of the specifics of our case, it does not appear convincing that the tumor primarily produced insulin because this was not reflective in the preoperative findings (normal C-peptide and serum insulin levels). A reasonable explanation could be that the tumor did produce IGF-2, functioning to symptomatically lower serum glucose levels. Unfortunately, there was never a preoperative serum evaluation for IGF-2, and pathologic examination at our facility could not stain for IFG-2 to prove this definitively. The only abnormal laboratory test result in the patient was an elevated proinsulin level, which has been described as a mechanism for tumor-induced hypoglycemia in previous cases, often termed proinsulinoma.5 Proinsulin is a biological precursor to insulin and has approximately 10% of the biologic activity of insulin.25 In a review of proinsulin-secreting tumors, Murtha et al5 described the specific diagnostic criteria for this symptomatic syndrome, including low levels of serum glucose, normal serum insulin concentrations, and C-peptide with elevated proinsulin levels, which would fit our patient. The authors point out, however, that all these identified tumors resided in the pancreas.5 Although a biopsy of the pancreas was performed in the present case, this was not the ideal evaluation to rule out a functional tumor of the pancreas because pancreatic vein sampling has been shown to be superior.7 If our patient’s tumor acted through proinsulin, it would be the first, to our knowledge, of a nonpancreatic NET to produce proinsulin causing systemic hypoglycemic syndrome. Unfortunately, proinsulin staining is not available at our institution, so this theory was impossible to confirm.26 Given the lack of symptoms after resection, it is still reasonable to infer that the cause of the patient’s hypoglycemia was his appendiceal tumor. The exact mechanism of the patient’s NET remains uncertain.


This case adds to the literature of the possible endocrine effects of a nonpancreatic NET that, to our knowledge, has not been previously described. Surgery with curative intent appears to be an effective therapy for these localized tumors that can be resected completely.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.


Kathleen Louden, ELS, of Louden Health Communications performed a primary copy edit.

Author Affiliations

1 Surgery Department, Saint Joseph Hospital, Denver, CO

2 Surgery Department, Kaiser Permanente Colorado, Denver

Corresponding Author

Peter F Layman, DO (

How to Cite this Article

Layman PF, Davis-Merritt D, Neff P. Primary functioning neuroendocrine tumor of the appendix with hypoglycemia syndrome: A case report and review of neuroendocrine tumors. Perm J 2020;23:19.142. DOI:

1.    McCusker ME, Coté TR, Clegg LX, Sobin LH. Primary malignant neoplasms of the appendix: A population-based study from the surveillance, epidemiology and end-results program, 1973-1998. Cancer 2002 Jun 15;94(12):3307-12. DOI: PMID:12115365
    2.    Pickhardt PJ, Levy AD, Rohrmann CA Jr, Kende Al. Primary neoplasms of the appendix: Radiologic spectrum of disease with pathologic correlation. Radiographics 2003 May-Jun;23(3):645-62. DOI: PMID:12740466
    3.    Moris D, Tsilimigras DI, Vagios S, et al. Neuroendocrine neoplasms of the appendix: A review of the literature. Anticancer Res 2018 Feb;38(2):601-11. DOI: PMID:29374682
    4.    Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): Results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010 Sep;21(9):1794-803. DOI:
    5.    Murtha TD, Lupsa BC, Majumdar S, Jain D, Salem RR. A systematic review of proinsulin-secreting pancreatic neuroendocrine tumors. J Gastrointest Surg 2017 Aug;21(8):1335-41. DOI: PMID:28510792
    6.    Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing but NET: A review of neuroendocrine tumors and carcinomas. Neoplasia 2017 Dec;19(12): 991–1002. DOI: PMID:29091800
    7.    Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016;103(2):153-71. DOI: PMID:26742109
    8.    Taal BG, Visser O. Epidemiology of neuroendocrine tumours. Neuroendocrinology. 2004;80 Suppl 1:3-7. DOI: PMID:15477707
    9.    Koch CA, Petersenn S. Black swans­—neuroendocrine tumors of rare locations. Rev Endocr Metab Disord 2018 Jun;19(2):111-121. DOI: PMID:30341705
    10.    Iglesias P, Díez JJ. Management of endocrine disease: A clinical update on tumor-induced hypoglycemia. Eur J Endocrinol 2014 Mar 14;170(4):R147-57. DOI: PMID:24459236
    11.    Shames JM, Dhurandhar NR, Blackard WG. Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med 1968 Apr;44(4):632-7. DOI: PMID:4296076
    12.    Kiang DT, Bauer GE, Kennedy BJ. Immunoassayable insulin in carcinoma of the cervix associated with hypoglycemia. Cancer 1973 Apr;31(4):801-5. DOI:<801::aid-cncr2820310407>;2-j PMID:4706048
    13.    Lyall SS, Marieb NJ, Wise JK, Cornog JL, Neville EC, Felig P. Hyperinsulinemic hypoglycemia associated with a neurofibrosarcoma. Arch Intern Med 1975 Jun;135(6):865-7. DOI: PMID:1130933
    14.    Shetty MR, Boghossian HM, Duffell D, Freel R, Gonzales JC. Tumor-induced hypoglycemia: A result of ectopic insulin production. Cancer 1982 May 1;49(9):1920-3. DOI:<1920::aid-cncr2820490927>;2-m
    15.    Fujino K, Yamamoto S, Matsumoto M, Sunada M, Ota T. Paraganglioma associated with hypoglycemia. Intern Med 1992 Oct;31(10):1239-41. DOI: PMID:1286235
    16.    Seckl MJ, Mulholland PJ, Bishop AE, et al. Hypoglycemia due to an insulin-secreting small-cell carcinoma of the cervix. N Engl J Med 1999 Sep 2;341(10):733-6. DOI: PMID:10471459
    17.    Hall K-F, Lin CL, Wang TH, Chang RH, Chen HM. A case of gastrointestinal stromal tumor with hyperinsulinemic hypoglycemia. Chang Gung Med J 2008 Jan-Feb;31(1):107-11. PMID:18419060
    18.    de Groot JW, Rikhov B, van Doom J, et al. Non-islet cell tumour-induced hypoglycaemia: A review of the literature including two new cases. Endocr Relat Cancer 2007 Dec;14(4):979-93. DOI: PMID:18045950
    19.    Ramkumar S, Dhingra A, Jyotsna VP, et al. Ectopic insulin secreting neuroendocrine tumor of kidney with recurrent hypoglycemia: A diagnostic dilemma. BMC Endocr Disord 2014;14: 36. DOI: PMID:24741994
    20.    Ida T, Morohashi T, Ohara H, et al. Gastric neuroendocrine carcinoma with non-islet cell tumor hypoglycemia associated with enhanced production of insulin-like growth factor II. Intern Med 2013;52(7):757-60. Epub 2013 Apr 1. DOI: PMID:23545670
    21.    Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med 1997 Feb 27;336(9):633-40. DOI: 0.1056/NEJM199702273360907 PMID:9032050
    22.    Daughaday WH, Emanuele MA, Brooks MH, et al. Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 1988 Dec 1;319(22):1434-40. DOI: PMID:3185662
    23.    Han G, Zhang Z, Shen X, et al. Doege-Potter syndrome: A review of the literature including a new case report. Medicine (Baltimore) 2017 Jul;96(27):e7417. DOI: PMID:28682900
    24.    Singh R, Grey A, Miller M, Gresnigt MG, Hoogerbrugge CM, van Doom J. Non-hyperinsulinemic hypoglycemia in a patient with a gastrointestinal stromal tumor. Eur J Intern Med. 2006 Mar;17(2):127-9. DOI: PMID:16490691
    25.    Kitabchi AE. Proinsulin and C-peptide: A review. Metabolism 1977 May;26(5):547-87. DOI: PMID:403392
    26.    Miraki-Moud F, Grossman AB, Besser M, Monson JP, Camacho-Hübner C. A rapid method for analyzing serum pro-insulin-like growth factor-II in patients with non-islet cell tumor hypoglycemia. J Clin Endocrinol Metab 2005 Jul;90(7):3819-23. DOI: PMID:15840753

Keywords: appendiceal neoplasm, hypoglycemia crisis, neuroendocrine tumors (NETs), non-islet cell tumor-induced hypoglycemia, proinsulin, symptomatic hypoglycemia, tumor-induced hypoglycemia


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