BMC Endocrine Disorders
This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted
PDF and full text (HTML) versions will be made available soon.
Ectopic insulin secreting neuroendocrine tumor of kidney with recurrent
hypoglycemia: a diagnostic dilemma
BMC Endocrine Disorders 2014, 14:36
doi:10.1186/1472-6823-14-36
S Ramkumar (ram.kumar@msn.com)
Atul Dhingra (dratuldhingra@gmail.com)
VP Jyotsna (vivekapjyotsna@yahoo.com)
Mohd Ashraf Ganie (ashraf.endo@gmail.com)
Chandan J Das (docchandan17@gmail.com)
Amlesh Seth (amlesh.seth@gmail.com)
Mehar C Sharma (sharmamehar@yahoo.co.in)
Chandra Sekhar Bal (csbal@hotmail.com)
ISSN
Article type
1472-6823
Case report
Submission date
23 December 2013
Acceptance date
6 March 2014
Publication date
17 April 2014
Article URL
http://www.biomedcentral.com/1472-6823/14/36
Like all articles in BMC journals, this peer-reviewed article can be downloaded, printed and
distributed freely for any purposes (see copyright notice below).
Articles in BMC journals are listed in PubMed and archived at PubMed Central.
For information about publishing your research in BMC journals or any BioMed Central journal, go to
http://www.biomedcentral.com/info/authors/
© 2014 Ramkumar et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Ectopic insulin secreting neuroendocrine tumor of
kidney with recurrent hypoglycemia: a diagnostic
dilemma
S Ramkumar1
Email: ram.kumar@msn.com
Atul Dhingra1
Email: dratuldhingra@gmail.com
VP Jyotsna1*
*
Corresponding author
Email: vivekapjyotsna@yahoo.com
Mohd. Ashraf Ganie1
Email: ashraf.endo@gmail.com
Chandan J Das2
Email: docchandan17@gmail.com
Amlesh Seth3
Email: amlesh.seth@gmail.com
Mehar C Sharma4
Email: sharmamehar@yahoo.co.in
Chandra Sekhar Bal5
Email: csbal@hotmail.com
1
Department of Endocrinology and Metabolism, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi 110029, India
2
Departments of Radiology, All India Institute of Medical Sciences, New Delhi,
India
3
Departments of Urology, All India Institute of Medical Sciences, New Delhi,
India
4
Departments of Pathology, All India Institute of Medical Sciences, New Delhi,
India
5
Departments of Nuclear Medicine, All India Institute of Medical Sciences, New
Delhi, India
Abstract
Background
Hypoglycemia secondary to ectopic insulin secretion of non-pancreatic tumors is rare.
Case presentation
We describe a middle aged woman with recurrent hypoglycemia. On evaluation, she was
detected to have hyperinsulinemic hypoglycemia and right sided renal mass lesion. 68GaDotanoc and 99mTc-HYNICTOC scans confirmed the intrarenal mass to be of
neuroendocrine origin. Right nephrectomy was done and it turned out to be an insulin
secreting neuroendocrine tumour. Neuroendocrine nature of this tumour was further
confirmed by ultra-structural examination. Her hypoglycemia did not recur after resection of
this tumour.
Conclusion
Few cases of ectopic insulin secretion have been reported though some are not proven
convincingly. This case addresses all the issues raised in previous case reports and proves by
clinical, laboratory, functional imaging and immunohistochemical analysis that ectopic origin
of insulin by non-pancreatic tumors does occur. To our knowledge, this is the first reported
case of ectopic insulinoma arising from the kidney.
Keywords
Hyperinsulinemic hypoglycemia, Neuroendocrine tumour, Insulinoma, Carcinoid tumor,
Renal tumour, 68Ga-Dotanoc scan, 99mTc-HYNICTOC scan
Background
The most common cause of endogenous hypoglycemia is hyperinsulinemia secondary to islet
cell tumours of pancreas. Hypoglycemia due to non-pancreatic tumours is infrequently
reported. Most of these non-pancreatic tumours secrete factors with insulin like activity.
Ectopic insulin secretion has been reported in few cases but not convincingly proved. We
report a case of ectopic insulin secretion by neuroendocrine tumour (NET) of kidney. The
ectopic origin of the tumour is demonstrated by functional imaging (68Ga-Dotanoc and 99mTcHYNICTOC), and by immunohistochemistry for insulin staining. We also extensively
reviewed literature for similar cases of ectopic insulin secreting tumours published
previously.
Case presentation
This 44-year- old female was admitted for evaluation of recurrent hypoglycemic episodes of
3 years duration. She had complains of forgetfulness, altered behaviour, headache,
palpitation, sweating, and giddiness. Most of her symptoms occurred early in the morning
and these symptoms improved spontaneously in 15 minutes. She had consulted various
physicians including neurologist and psychiatrist and had been diagnosed as pseudo-seizure,
panic attacks or conversion disorder. One year back, she consulted endocrinologist and was
diagnosed to have hypoglycemia and hyperinsulinemia. For suspecting insulinoma, she
underwent CT abdomen which showed a right renal mass lesion and possibility of renal cell
carcinoma was entertained. She was advised surgery for renal tumour. However, patient did
not agree for surgery. There were no complains of hematuria, urinary frequency, urgency,
burning micturition, diarrhoea or flushing episodes. She was not on antidiabetic treatment and
was not hypertensive. For last 2 months, patient was having recurrent hypoglycemic seizures
and came to this hospital.
After admission, she had persisted hypoglycemia and required continuous infusion of 10%
Dextrose at the rate of 75 – 100 ml/hr in addition to 1-2 hourly feeds. Her hemogram,
electrolytes, renal and liver functions were normal. HbA1c was 4.5%. Hormonal assay
showed thyroxine (T4) 5.67(5.1 – 14.1mcg/dl), TSH 4.42(0.27 – 4.2 mIU/ml), Insulin like
Growth Factor- I(IGF-1) - 165.90(62 – 205 ng/ml), growth hormone 1.20 ng/ml and cortisol
15.78 mcg/dl. Samples collected during hypoglycemia showed a serum insulin of 134 (2.6 –
24.9 µU/ml) and C-peptide of 13.35 (1.1 – 4.4) ng/ml. During another symptomatic
hypoglycemia, she had plasma glucose of 44 mg/dl while her plasma insulin and C-peptide
were 49.81 miu/ml and 9.36 ng/ml respectively confirming endogenous hyperinsulinemic
hypoglycemia. She underwent high resolution radiological and functional imaging for
localisation of insulinoma.
Both multi-phase CT abdomen (Figure 1) and contrast enhanced MRI abdomen demonstrated
a mass lesion arising from upper- mid pole of right kidney (Figure 1a, 1b, 1c). No lesion was
identified in the pancreas (Figure 1d). Endoscopic ultrasound also did not demonstrate any
pancreatic lesion. 68Gallium DOTANOC scan (Figure 2a-c) and 99mTc-HYNICTOC
(Figure 2d,e) did not demonstrate any uptake in the pancreas but both demonstrated intense
uptake in the mass lesion indicating a NET. She underwent abdominal exploration and right
nephrectomy. Post-operative period was uneventful and she became euglycemic without need
for dextrose infusion. Her glucose values were maintained between 120 – 160 mg/dl thus
confirming the right sided mass near renal hilum to be the source of ectopic insulin secretion.
Figure 1 CT scan. Unenhanced CT axial image (1a) showing an isodense mass (arrow) to
renal parenchyma which show enhancement in arterial phase image (1b) but lesser than the
renal cortex. The enhancement continued till the venous phase (1c). Arterial phase image
(1d) taken at the level of pancreas (arrow) did not show any arterial enhancing lesion.
Figure 2 Nuclear scans. 3 mCi of 68Ga-Dotanoc PET/CT scan demonstrates somatostatin
receptor (SSTR) expressing an intrarenal mass (2a) that corresponds to NCCT mass (2b).
There was no abnormal SSTR expressing tumour in pancreas (2c), or any other abdominal
structure. Similar observation was initially made from 15 mCi of 99mTc-HYNICTOC
SPECT/CT scanning (2d, 2e).
Pathologic examination
Gross examination: Grossly the kidney measured10x7x6 cm and weighed 350 gram. A solid
well circumscribed yellowish tumour, measuring 7x6x5 cm, was identified in the upper pole
of kidney (Figure 3a). There was no capsule breach or renal sinus infiltration. Rest of the
renal parenchyma and pelvicalyceal system were unremarkable. Areas of necrosis or
hemorrhage were not identified.
Figure 3 Histopathology. Gross photomicrograph showing a yellow colored well
circumscribed tumour in the upper pole of the kidney (3a). Photomicrographs showing
diffuse and trabecular arrangement of tumour cells (3b, 3c & 3d) with marked desmoplastic
reaction at places (3e). (3b, 3c & 3d: H&E x 400 each, 3e: H&E x 200). Tumour cells are
immunoreactive to chromogranin, synaptophysin and insulin (3f, 3g, 3h x 400 each). MIB 1
LI is 2% (d3i x 200). Electron micrographs showing numerous membrane bound electron
dense neurosecretory granules, mitochondria and prominent rough endoplasmic reticulum (3j
x2550; 3k x9000 original magnification).
Microscopic Finding: Microscopically, the tumor was composed of solid nests anastomosing
cords and trabeculae of low columnar cells separated by a vascular stroma [Figures 3b-d].
The cellular outlines were indistinct with centrally placed oval nuclei, fine chromatin and
inconspicuous nucleoli. The cytoplasm was eosinophilic, finely granular and moderate in
amount. At places there were intense desmoplasia around the tumor cells (Figure 3e). Mitotic
rate was 1 per 10 high power fields (hpf). Areas of tumour necrosis were not identified. Foci
of perineural, lymphatic and vascular invasion were not seen. No intra or extra-cellular mucin
was identified. Immunohistochemical staining revealed diffuse and intense staining for
pancytokeratin, synaptophysin, chromogranin A, neuron specific enolase (NSE) and insulin
(Figure 3f, 3 g, 3 h). MIB I labeling index was 2% (Figure 3i). The lymph nodes dissected
from the specimen show metastasis (2/3)
Ultrastructural examination revealed numerous electron dense, membrane bound round to
oval shaped granules of variable diameter in the cytoplasm [Figure 3j, 3k]. A narrow
peripheral lighter zone was present in some of the granules.
Based on the above features; the diagnosis neuroendocrine tumour grade G1; pathological
stage IV was entertained. Serum chromogranin A measured in the samples collected before
surgery and stored in -40 degree was 2126.1(N < 90.1 ng/ml).
Follow up
No metastasis was detected. Our patient got discharged in stable condition on 10th postoperative day. The patient is asymptomatic, euglycemic and disease free at last follow-up at 3
months.
Discussion
Islet cell tumours of pancreas produce insulin which cause hypoglycemia. Hypoglycemia due
to non-pancreatic tumours is infrequently reported and poorly understood. Various
mechanisms were proposed [1] are: (a) insulin or insulin-like activity produced by the
tumour, (b) decreased gluconeogenesis, (c) disruption of glucagon metabolism, and (d)
increased utilization of glucose by the tumour. The non-suppressible Insulin like Activity
(NSILA) has been purposed to be secondary to Insulin like Growth Factor-2. The non-islet
cell tumours which commonly cause hypoglycaemia are of mesenchymal, epithelial or
hematopoietic cell lines. Fibrosarcomas, mesotheliomas, leiomyosarcomas, and
hemangiopericytomas are the most frequent types of tumours which cause hypoglycemia.
Hepatoma, gastric, pancreatic, exocrine gland and lung carcinomas are epithelial cancers with
frequent hypoglycemic potential. Mesenchymal and epithelial tumors, which generally
present as large masses, are located in the mediastinum or the abdomen. These tumours are
known to cause hypoglycemia via secretion of IGF-2 that leads to stimulation of insulin
receptors [2]. In a series of 78 cases of non-islet-cell tumour, hypoglycemia (NICTH) due to
IGF-2 production, hepatocellular carcinoma and gastric carcinoma were the common causes
[3].
Ectopic insulin secreting tumours are rare, comprising only 1% to 2% of all insulinomas [4]
and are commonly located in the peripancreatic or periduodenal region where most
heterotopic pancreatic tissue is located. Ectopic insulin producing tumours located away from
pancreatic beds are infrequently reported in literature. Only few cases were described in
literature due to hyperinsulinemic hypoglycemia and non-pancreatic tumour and these tumors
are described in Table 1.
Table 1 Insulin secreting extra-pancreatic tumors reported in literature
Evidence of hyperinsulinemiaa in tumour
Case
1
Ovarian carcinoid [5]
2
Carcinoma cervix [6]
3
Bronchial carcinoid [7]
Resolution of
hypoglycemia after
resection of tumour
Insulin staining(5%), EM – beta cell granules, Not demonstrated
absence of pancreatic tumor at autopsy
Insulin staining, absence of pancreatic tumor at Not demonstrated
autopsy
Insulin staining
Not demonstrated
4
Paraganglioma [8]
None
Yes
HPE
5
Paraganglioma [9]
Insulin staining (3%)
Yes
HPE
6
Pheochromocytoma [10]
Insulin stain negative, absence of pancreatic
tumor at autopsy
Not demonstrated
HPE
7
Neuroendocrine tumor of liver
[11]
Insulin staining, absence of any extrahepatic
tumor at autopsy, Selective arterial calcium
stimulation
Insulin staining, EM – beta cell granules,
Not demonstrated
HPE
Mechanism of hypoglycemia
-proposed
HPE
Direct tumoral secretion of
insulin
Liver metastasisb, Direct
tumoral secretion of insulin
Liver metastasisc, Direct
tumoral secretion of insulin
No conclusive evidence of
direct tumoral secretion of
insulin
Direct tumoral secretion of
insulin
Beta adrenoceptor mediated
release of insulin from
pancreas
Direct tumoral secretion of
insulind
HPE
HPE
HPE, 68 Gallium
Direct tumoral secretion of
DOTANOC, HYNICTOC insulin
imaging
a
Includes evidences other than biochemical documentation of hyperinsulinemia in critical samples(collected at the time of hypoglycemia).
b
Liver functions are reportedly normal in this patient.
c
70% of the liver was replaced by tumor at autopsy in this patient.
d
This patient developed hypoglycemia after left hepatectomy.
HPE – Histo-pathological examination, EM – Electron Microscopy.
8
Neuroendocrine tumour
kidney(carcinoid) (Present case)
Yes
Evidence of neuroendocrine origin
The patient under discussion had presented with right renal mass lesion and hyperinsulinemic
hypoglycemia. We initially considered the possibility of incidentally detected right renal cell
carcinoma in patient with insulinoma. In our Institute, we have both PET and SPECT
imaging agents for octreoscan available for the localisation of insulinoma. Somatostain
receptor scintigraphy (SRS) is an established functional imaging method for patients with
NETs. The sensitivity of SRS for insulinoma is 50 – 60% [12]. We did both 68Ga-Dotanoc
and 99mTc-HYNICTOC scans for the localisation of insulinoma which unexpectedly revealed
increased uptake in the right renal mass lesion itself confirming it to be a NET. To the best of
our knowledge, this is the first case of ectopic insulin secretion confirmed in vivo by 68GaDotanoc and 99mTc-HYNICTOC scan. Further, the neuroendocrine and insulin secreting
nature of the tumour was confirmed ex vivo by histopathological examination,
immunohistochemistry
and
ultra-structural
examination.
Paraganglioma
and
pheochromoctyoma were also reported to cause hyperinsulinemic hypoglycemia and also
show tracer uptake by SRS and are immunoreactive for chromogranin A and syanptophysin.
Though the mass lesion was arising from upper pole of right kidney, it was intra-renal and
hisopathological examination was suggestive of NET.
NETs are neoplasms that arise from cells of dispersed neuroendocrine system. Although there
are many kinds of NETs but they are treated as a group of tumours as these neoplasms share
common features such as histology, immunoreactivity for neuroendocrine markers
(chromogranin A, synaptophysin, neuron specific enolase), presence of neurosecretory
granules, and secretion of biogenic amines and polypeptide hormones. Neuroendocrine
tumours arising from pancreas are classified by the hormone most commonly secreted.
Neuroendocrine tumours arising from the intestine, respiratory system and rest of the body
were known as carcinoids but under the recent nomenclature they are all know as
neuroendocrine neoplasm (NEN) of tumour. Primary carcinoid tumours of kidney are
extremely rare and around 90 cases has been reported in literature [13]. None of the reported
cases including two cases were reported from our institute previously [14,15] were insulin
secreting.
The cell of origin of renal carcinoid is unclear as neuroendocrine cells are not normally found
in adult renal parenchyma. Carcinoid tumours of kidney are usually asymptomatic. In
symptomatic cases, these tumours present with abdominal pain or abdominal mass with
hematuria or fever. Evidence of carcinoid syndrome with serotonin-related flushing,
generalized edema and diarrhoea, and occasional elevation of urine 5hydroxyindoleaceticacid are uncommon and are seen in less than 10% of cases [14]. Our
patient did not have these symptoms prior to presentation, although she had flushing, edema
and blanching of the skin intraoperatively. Rarely, these tumours may present with
neuroendocrine syndromes like cushing syndrome, vipoma, or glucagonoma [16]. Our case
presented as insulinoma. Macroscopically, renal carcinoid tumours are usually solitary and
unilateral. They are well circumscribed with a lobulated and bulging appearance. The cut
surface the tumour is yellow-tan, or red brown as also observed in the case under discussion.
Renal carcinoids exhibit histological features that are typical of carcinoids at other sites.
Primary carcinoid tumors as well as metastasis possess high affinity receptors for
somatostatin in 87% of cases [17]. Localization of gastrointestinal tract carcinoid tumours
and pancreatic endocrine tumors has been achieved by the use of radiolabeled octreotide, a
synthetic and slowly degraded somatostatin analogue that has a high affinity for somatostatin
receptors. Use of indium-111 pentetreotide scanning in the diagnosis of carcinoid tumors had
been reported [18]. In the present case, functional imaging with 68Ga-Dotanoc and 99mTcHYNICTOC was done for the localisation of insulinoma. Both showed uptake in the right
renal mass lesion and no uptake in pancreas (Figure 2a-e). All available modalities for
diagnosis of carcinoid tumors were employed namely Electron microscopy,
immunohistochemistry, both PET and SPECT octreotide scan along with conventional
radiographic imaging techniques were used in preoperative diagnosis this tumour.
Prognosis of NET depends upon the grade and stage of the tumour. Although the grade of the
tumour was low, however stage was high as there was metastasis in the regional lymph
nodes. There was no recurrence of hypoglycaemia on till this time of reporting, however,
long-term close follow up is needed for the malignant behaviour.
Conclusions
Ectopic insulin secreting extra-pancreatic tumours are rare. Confirmation of the source of
hyperinsulinemia is often difficult. To our knowledge, this is the first case of extra-pancreatic
insulin secreting neuroendocrine tumour fully characterised by biochemical, radiological &
functional imaging, histopathology and immunohistochemistry. Our patient had successful
post-operative outcome and maintained euglycaemia after three months of follow-up.
Consent
Written informed consent was obtained from the patient for publication of this Case report
and any accompanying images. A copy of the written consent is available for review by the
Editor of this journal.
Abbreviations
SRS, Somatostain receptor scintigraphy; NEN, Neuroendocrine neoplasm; NICTH, Nonislet-cell tumour hypoglycemia; NET, Neuroendocrine tumor
Competing interest
The authors declare that they have no competing interest.
Author contributions
1) RS, JVP, DA, GMA have managed the case clinically with the help of DCJ (radiology),
BCS (Nuclear Medicine), SMC (pathology) and SA (Uro-Surgery) for diagnosis and
management. DCJ has done and reported the CT scans, BCS has done and reported the
Nuclear scans (68Ga-Dotanoc PET/CT and 99mTc-HYNICTOC SPECT/CT scans), SMC
has done the ultrastructural examination and immunostaining while SA has performed the
definitive surgery which was curative in this case.2) RS And DA have been involved in
drafting the manuscript and JVP in revising it critically for important intellectual content. 3)
All authors have given final approval of the version to be published.
References
1. Immerman SC, Sener SF, Khandekar JD: Causes and evaluation of tumor-induced
hypoglycemia. Arch Surg 1982, 117:905–908.
2. Daughaday WH, Trivedi B: Measurement of derivatives of proinsulin-like growth
factor-II in serum by a radioimmunoassay directed against the E-domain in normal
subjects and patients with nonislet cell tumor hypoglycemia. J Clin Endocrinol Metab
1992, 75:110–115.
3. Fakuda I, Hizuka N, Ishikawa Y, Yasumoto K, Murakami Y, Sata A, Morita J, Kurimoto
M, Okubo Y, Takano K: Clinical features of insulin-like growth factor-II producing nonislet-cell tumor hypoglycemia. Growth Horm IGF Res 2006, 16:211–216.
4. Filipi CJ, Higgins GA: Diagnosis and management of insulinoma. Am J Surg 1973,
125:231–239.
5. Morgello S, Schwartz E, Horwith M, King ME, Gorden P, Alonso DR: Ectopic insulin
production by a primary ovarian carcinoid. Cancer 1988, 61:800–805.
6. Seckl MJ, Mulholland PJ, Bishop AE, Teale JD, Hales CN, Glaser M, Watkins S, Seckl
JR: Hypoglycemia due to an insulin-secreting small-cell carcinoma of the cervix. N Engl
J Med 1999, 341:733–736.
7. Shames JM, Dhurandhar NR, Blackard WG: Insulin-secreting bronchial carcinoid
tumor with widespread metastases. Am J Med 1968, 44:632–637.
8. Fujino K, Yamamoto S, Matsumoto M, Su-nada M, Ota T: Paraganglioma associated
with hypoglycemia. Intern Med 1992, 31:1239–1241.
9. Uysal M, Temiz S, Gul N, Yarman S, Tanakol R, Kapran Y: Hypoglycemia due to
ectopic release of insulin from a Paraganglioma. Horm Res 2007, 67:292–295.
10. Frankton S, Baithun S, Husain E, Davis K, Grossman AB: Pheochromocytoma crisis
presenting with profound hypoglycemia and subsequent hypertension. Hormones 2009,
8:65–70.
11. McCaffrey JA, Reuter VV, Herr HW, Macapinlac HA, Russo P, Motzer RJ: Carcinoid
tumor of the kidney the use of somatostatin receptor scintigraphy in diagnosis and
management. Urol Oncol 2005, 5:108–111.
12. Sundin A, Garske U, Orlefors H: Nuclear imaging of neuroendocrine tumours. Best
Pract Res Clin Endocrinol Metab 2007, 21(1):69–85.
13. Armah HB, Parwani AV: Primary carcinoid tumor arising within mature teratoma of
the kidney. Report of a rare entity and review of the literature. Diagn Pathol 2007, 2:15.
14. Jain D, Sharma MC, Singh K, Gupta NP: Primary carcinoid tumor of the kidney: case
report and brief review of the literature. Indian J Pathol Microbiol 2010, 53(4):772.
15. Singh PP, Malhotra AS, Kashyap V: Carcinoid tumor of the kidney: an unusual renal
tumor. Indian J Urol 2009, 25:537–538.
16. Korkmaz T, Seber S, Yavuzer D, Gumus M, Turhal NS: Primary renal carcinoid:
treatment and prognosis. Crit Rev Oncol Hematol 2013, 87:256–264.
17. Reubi JC, Kvols LK, Waser B, Nagorney DM, Heitz PU, Charboneau JW, Reading CC,
Moertel C: Detection of somatostatin receptors in surgical and percutaneous needle
biopsy samples of carcinoids and islet cell tumors. Cancer Res 1990, 50:5969–5973.
18. McCaffrey JA, Reuter VV, Herr HW, Macapinlac HA, Russo P, Motzer RJ: Carcinoid
tumor of the kidney the use of somatostatin receptor scintigraphy in diagnosis and
management. Urol Oncol 2005, 5:108–111.
View publication stats