Case presentation: Endogenous hyperinsulinaemic hypoglycaemia is most commonly attributed
to pancreatic islet-cell tumours. We present a case of an
insulin-secreting cervical neuroendocrine carcinoma causing significant
hypoglycaemia.
A 62 year-old postmenopausal female presented with postcoital bleeding,
on a background of two normal vaginal childbirths, tubal ligation and
menopause at age 42. She had no other significant medical history, was a
lifelong non-smoker, did not drink alcohol, and took no prescribed
medications. Vaginal speculum examination, followed by hysteroscopy,
demonstrated a tumour of the cervical lip. Papanicolaou smear and biopsy
confirmed a human papilloma virus-18 positive cervical cancer. There
were intermediate size, malignant cells with oval, hyperchromatic and
overlapping nuclei, frequent mitosis, and necrosis. Tumour cells stained
positively for p16, CD56 and synaptophysin, consistent with a
neuroendocrine tumour.
Ultrasound, computed tomography (CT) and FDG-positron emission
tomography (PET) confirmed a 3x4cm cervical mass without nodal or
distant metastases, and a diagnosis of Stage IB2 neuroendocrine
carcinoma of the cervix was made. She completed six cycles of
carboplatin and etoposide with curative intent, followed by external
beam radiotherapy and brachytherapy with a total biological equivalent
dose of 90.8 Gy. A restaging FDG-PET scan prior to completion of
chemotherapy showed incomplete metabolic response in the cervix, but no
local nodal or metastatic disease. Post-treatment biopsy demonstrated a
tumour comprised of intermediated size neoplastic cells arranged in a
nested pattern [Figure 1a]. The tumour cells demonstrated
neuroendocrine differentiation and a Ki-67 proliferation index of 30%.
At 12 months post-diagnosis, the patient presented to the emergency
department with an episode of symptomatic hypoglycaemia (plasma glucose
1.7mmol/L) occurring in the fasted state. She was not receiving any
antidiabetic treatment. She exhibited sinus tachycardia to 120bpm,
sweating and tremor. Symptoms were promptly corrected by administration
of glucose, fulfilling Whipple’s triad. The patient also demonstrated
marked pitting oedema of the lower limbs without evidence of cardiac
failure. Biochemical studies demonstrated normal renal function
(estimated glomerular filtration rate >90) and
electrolytes, but marked liver function derangement, hypoalbuminaemia to
21g/L [normal range 35-50], normocytic anaemia to 75g/L [normal
range 115-165] and thrombocytopenia to 25 x 109g/L
[normal range 150-400]. During one episode of recurrent
hypoglycaemia, when plasma glucose was 2.2mmol/L, serum c-peptide was
2.33nmol/L [normal range 0.26-1.73] and serum insulin 19mIU/L
[normal range <9]. Chest x-ray revealed widespread
cannonball pulmonary metastases [Figure 2 ] and computed
tomography revealed hepatic metastases, persistence of the cervical
mass, and no evidence of a pancreatic lesion. Retrospective review of
the cervical biopsy with further immunohistochemistry revealed positive
straining for insulin and negative staining for glucagon confirming that
her symptoms were due to an insulin-secreting neuroendocrine carcinoma
(NEC) [Figure 1b ].
Initial treatment with intravenous boluses of 50% dextrose, maintenance
10% dextrose and intravenous hydrocortisone 100mg QID were insufficient
to maintain normoglycaemia. Based on suspicions of an insulin-secreting
neuroendocrine carcinoma, the subcutaneous somatostatin analogue
octreotide was commenced at 200mcg q8hrly. This allowed the cessation of
intravenous dextrose and hydrocortisone and clinically significant
improvement in hypoglycaemia. Acute hypoglycaemic events were managed
with oral glucose and PRN subcutaneous glucagon 1mg. In view of
progressing aggressive malignancy and poor performance status a
palliative approach to management was decided. The patient died on day
20 of admission.
Neuroendocrine neoplasms (NENs) are malignancies that arise from
neuroendocrine cells and may have the ability to produce and secrete
peptide hormones. They typically originate in lung, gastro-intestinal
tract or pancreas. NENs of the uterine cervix are rare and account for
0.9-1.5% of all cervical cancers1. Recent updates to
the classification of NEN, which emphasise tumour grade as opposed to
anatomical origin, distinguish low-grade neuroendocrine tumours from
high-grade NECs2. Large cell NECs, as in this case,
are less common than small cell NECs and are characterised
morphologically by cells which are organised in organoid or trabecular
patterns, with abundant cytoplasm, large nuclei with prominent nucleoli
and high mitotic rate. Large cell NECs usually have relatively lower
Ki-67 proliferation index compared to small cell NECs which always
demonstrate >90% proliferation index. Diagnosis is
confirmed by positive immunohistochemistry for neuroendocrine markers
(synaptophysin, CD56 and chromogranin).
Staging is determined by the International Federation of Gynecology and
Obstetrics (FIGO) system3. Our patient at time of
diagnosis had a 3x4cm primary lesion of the uterine cervix without nodal
or distant metastases detected by PET. In conjunction with tissue
morphology and immunohistochemistry, this supports a diagnosis of a
Stage 1B2 large-cell neuroendocrine carcinoma of the cervix.
Due to the rarity of cervical NECs, no randomised controlled trials have
been undertaken to guide management. Instead treatment is informed by
retrospective studies and treatment approaches extrapolated from the
treatment of NEN arising from other organs such as small cell lung
cancers. Typically a multi-modal approach is utilised involving radical
surgery, radiotherapy and chemotherapy involving etoposide and either
carboplatin or cisplatin. Despite therapy, prognosis for cervical NECs
remain poor, with a 5 year survival of 36%4.
Non-islet cell tumours secreting insulin are infrequently reported, and
comprise 1-2% of insulinomas5, most commonly arising
in peripancreatic or periduodenal regions. Ectopic insulin-secretion has
been reported in phaeochromocytomas, and NENs of the kidney, liver,
ovary, lung and cervix5. Positive insulin
immunohistochemistry in the tumour, in combination with elevated
c-peptide and insulin levels suggests that the insulin-secreting tumour
was the aetiology for the patient’s hypoglycaemia. Interestingly, there
had been no previous history of symptomatic hypoglycaemia in the year
since diagnosis and it is likely that declining hepatic gluconeogenesis
due to an increasing metastatic tumour burden was a contributing factor
in the pathophysiology. We are aware of only two previously reported
cases6-7 of insulin-induced hypoglycaemia originating
from a cervical NEN, one of which was small-cell, and the other a
squamous cell carcinoma, although notably large-cell NECs were
frequently under-recognised and misdiagnosed as squamous cell carcinomas
at the time of its report7. In one patient, octreotide
offered minimal clinical improvement and she required diazoxide and
intravenous glucose6. While resection of insulinoma is
treatment of choice, medical therapy is considered for unresectable
metastatic disease or poor surgical candidates. Diazoxide inhibits
β-cell insulin release and enhances glycogenolysis, however was not used
in our patient due to her generalised oedema and the propensity for
diazoxide to cause fluid retention9. Octreotide binds
to somatostatin receptor type 2 and inhibits insulin, among other
hormones9. Phenytoin and verapamil also inhibit
insulin release and have been used with varied
success9. Endoscopic ultrasound-guided ethanol
ablation and CT-guided radiofrequency ablation of pancreatic insulinomas
are minimally invasive procedures also considered in poor surgical
candidates10-11.
Ectopic insulin-secreting neuroendocrine tumours are exceedingly rare,
but should be considered as a differential diagnosis for
hyperinsulinaemic hypoglycaemia.