David
Hill. Diabetes Centre, Gartnaval General Hospital, Glasgow.
Kerry
Livingstone. Diabetes Centre, Cumberland Infirmary, Carlisle.
James
E Thomson. Diabetes Centre, Inverclyde Royal Hospital, Greenock.
Colin
Perry. Department of Medicine, Glasgow Royal Infirmary, Glasgow.
Gwen Wark. Clinical Laboratory, Royal Surrey County Hospital, Guildford.
Corresponding
Author: David Hill.
Diabetes Centre, Gartnaval General Hospital, 1053 Great Western Road,
Glasgow, G12 0XH.
SMJ 2008 53(1): 60
Abstract
We report the case of an 84-year-old man who presented with collapse
secondary to hypoglycaemia and was found to have a hepatic Solitary Fibrous
Tumour (SFT) secreting Insulin-like Growth Factor II (IGF-II).
Solitary fibrous tumours of the liver are very rare tumours and have
occasionally been described in association with hypoglycaemia. SFT’s of other
organs have been associated with production of IGF-II but to our knowledge
however there are no reports of a SFT of the liver with confirmed IGF-II
hypersecretion, and we suggest that this mechanism underlies the hypoglycaemia
seen in this case.
Case
Report
An 84-year-old man with a past history of benign prostatic hypertrophy
and cerebrovascular disease was admitted to the acute medical receiving unit
with an episode of collapse. He was
confused and drowsy on admission and was noted to have laboratory plasma glucose
of 0.8mmol/L. There was a rapid
response to a 50ml intravenous bolus of 50% glucose solution.
The patient was not on insulin or oral hypoglycaemic agents and had no
history of diabetes. He had no known access to hypoglycaemic drug therapy.
On physical examination he appeared generally frail and was
found to have 3cm hepatomegaly. Computed
tomography (CT) brain scan showed marked cerebral atrophy.
He was anaemic (Haemoglobin 8.7 g/dl) with normal mean cell volume (87
fl) but low iron indices indicating iron deficiency
(iron 8 µmol/l (14-31); transferrin 2.1 g/l (2-3.6);
transferrin saturation 15% (25-50); ferritin 28 (30-400). There was mild
hyponatraemia (128mmol/l), hypoalbuminaemia (28 g/l), and mild elevation of
Alkaline Phosphatase at 477 IU/L (70-314). Short Synacthen test was normal.
Contrast enhanced CT scan of abdomen and thorax showed a 10x10x12cm well
encapsulated mass bridging the right and left lobes of liver and compressing
hilum and bile ducts (figure 1). A small right-sided pleural effusion was noted.
Three months previously he had been admitted under the care of the
urologists with acute urinary retention and was found to have histologically
proven benign prostatic hypertrophy at transurethral resection.
Abdominal ultrasound carried out at that time showed him to have a 12cm
liver mass. Liver biopsy showed a
spindle cell tumour with bland, elongated nuclei and sparse mitotic figures
(Figure 2). Some areas of the
tumour were cellular and others more collagenous. The tumour cells stained
strongly positive for CD34, BCL2 and vimentin but negative for cytokeratin,
smooth muscle actin, S100, protein melan A and CD117.
The histological features and staining were felt to be typical of a
Solitary Fibrous Tumour (SFT). No
further action was taken at this time as he was asymptomatic and the tumour was
felt to be benign.
During his admission the patient continued to develop hypoglycaemia,
increasing in frequency. During a
hypoglycaemic event (plasma glucose 1.7mmol/L), Insulin, C-Peptide, IGF-I
(Insulin like growth factor I) and IGF-II were measured.
Insulin and C-Peptide levels were suppressed; IGF-I: 4.2nmol/L (reference
range: 6.0 – 36.0); IGF-II 100nmol/L; IGF-II:IGF-I ratio: 23.8 (ref range
<10). These results were
consistent with IGF-II secreting tumour related hypoglycaemia.
The patient was not fit enough for surgical resection of the tumour and
despite treatment with octreotide, diazoxide and corticosteroids continued to
have recurrent severe hypoglycaemia. He
developed swallowing difficulties thought to be due to small vessel
disease/cerebral atrophy and eventually died.
Post mortem examination revealed bilateral pleural effusions, pulmonary
oedema and congestion, and the liver tumour was again examined and found to be
consistent with a SFT of liver.
Discussion
Solitary fibrous tumours are rare and even less commonly affect the
liver. Originally thought to
predominantly affect the pleura, they have also been found in the pericardium
and peritoneum but also non-serosal sites such as the orbit, lung parenchyma,
thyroid, adrenal gland, parotid gland, spinal cord, pancreas, renal capsule and
uterus.1
Presenting features include weight loss, nausea, vomiting and abdominal
fullness or the finding of a mass in an asymptomatic patient. Females appear to
be more commonly affected than males with a ratio of approximately 2:1 and the
age of presentation appears to be varied. Histiogenesis
of SFT remains controversial but is thought to be most likely mesenchymal in
origin. Tumours found have ranged
from 2-24cm in maximum diameter.2
Macroscopically SFT are firm, fibrous, sometimes-cystic tumours and are
usually well defined or encapsulated. Microscopically
they consist of strands of spindle cells with bland,
uniform, elongated nuclei admixed with collagen fibres and arranged in a
parallel and interwoven pattern with areas of both high and low cellularity.
Cellular atypia and necrosis are variably seen and mitotic figures have
also been noted in some cases. SFT
are therefore felt to have malignant potential but as far as we are aware from
the literature there have been no actual cases of SFT of liver reported with
associated or subsequent metastatic deposits.
Positive
immunohistochemical staining with CD34 and Vimentin are characteristic of SFT
while staining for smooth muscle actin, CD10, CD99, desmin, cytokeratin and
S-100 protein are negative.
SFT's producing hypoglycaemia secondary to IGF-II
expression by the tumour belong to the syndrome known as non-islet cell tumour
hypoglycaemia (NICTH). Diagnosis is
characterised by hypoglycaemia, suppressed serum insulin, C-peptide and growth
hormone and low serum IGF-I but normal or elevated serum levels of IGF-II.3
Often these tumours are associated with producing high molecular weight
IGF-II (big IGF-II).
Hypoglycaemia
can appear at any time in these malignancies and nothing is known about the
trigger that causes the production of IGF-II.
The resulting increase in IGF-II causes hypoglycaemia by enhancing the
disposal of glucose into muscle and inhibiting hepatic gluconeogenesis.4
Surgical
removal of the tumour results in resolution of symptoms of hypoglycaemia and
normalisation of biochemical markers. Where
surgery is not possible glucocorticoids have been shown to provide symptomatic
relief in NICTH.3 Therapeutic
human Growth Hormone is also thought to be beneficial, however it also
stimulates IGF-II and may be potentially hazardous in the long-term.
Most
cases in the literature of liver SFT’s were treated with surgical resection
and while there were no reports of tumour recurrence some patients died in the
post-operative period. Such
patients all had large tumours that were producing significant symptoms such as
pain, weight loss or hypoglycaemia.
Reviewing the literature we found around 30 cases of SFT’s associated
with hypoglycaemia1,2,5-8 and a number of cases have shown results
biochemically and pathologically consistent with IGF-II excretion from the
tumour.8 These have
mainly been intrathoracic.1 To
our knowledge no cases of SFT of the liver have biochemical or pathological
evidence of IGF-II secretion from the tumour although some have been associated
with hypoglycaemia.
In
summary, we present the case of an 84 year-old male who presented with severe
hypoglycaemia and a solitary fibrous tumour of the liver. IGF-II secretion was
noted to be significantly elevated, and we propose that this mediated the
hypoglycaemia seen in this patient, and may also explain the finding of
hypoglycaemia seen in other patients with this rare tumour.
References
Neoplasms causing non-hyperinsulinaemic hypoglycaemia. Lloyd RV, Erickson LA, Nasimento AG et al. Endocrine Pathology 1999;10: pp291-7
Solitary fibrous tumours of the liver: A clinicopathologic and immunohistochemical study of nine cases. Cesar A Moran, Kamal G Ishak. Annals of Diagnostic Pathology, Vol 2, No 1 (February), 1998. pp19-24
Glucocorticoid therapy suppresses abnormal secretion of big IGF II by NICTH. Teale and Marks. Clinical Endocrinology. Vol 49;1998; pp491-98
Insulin-like Growth Factors. Roith. NEJM. Vol 336;1997; pp633-40
Solitary Fibrous tumours of the liver. Ying-Tsun Lin, Gin-Ho Lo. Chinese Medical Journal (Taipei) 2001; 64: pp305-309.
Solitary Fibrous Tumour of the Liver with Presenting Symptoms of Hypoglycaemic Coma. Mamata Chithriki, Moneer Jaibaji. The American Surgeon, vol 70, pp291-293, April 2004.
Solitary Fibrous Tumour of the Liver with CD 34 Positivity and Hypoglycaemia. Alfredo Gugliemi, Matteo Frameglia. Journal of Hepato Biliary Pancreatic Surgery (1998) 5: pp212-216
Solitary Fibrous tumour of the uterus producing high-molecular weight Insulin-like Growth Factor II and Associated with hypoglycaemia. Kasuko et al. International Journal of Gynaecological Pathology (2005) vol 24. pp79-84