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Treatment of haemangiopericytoma-associated hypoglycaemia with embolisation
European Journal of Internal Medicine 13 (2002) 340–343 www.elsevier.com / locate / ejim
Brief report
Treatment of haemangiopericytoma-associated hypoglycaemia with embolisation P.W.B. Nanayakkara a , J. van Doorn b , F.G. van den Berg c , C.J. van Groeningen a , H.M. Pinedo a , a, K. Hoekman * a
Department of Medical Oncology, Vrije Universiteit Medische Centrum, Postbus 7075, 1007 MB Amsterdam, The Netherlands b Laboratory of Endocrinology, Wilhelmina Children’ s Hospital, University Medical Centre, Utrecht, The Netherlands c Department of Radiology, Vrije Universiteit Medische Centrum, Amsterdam, The Netherlands Received 13 August 2001; received in revised form 21 January 2002; accepted 4 April 2002
Abstract A 48-year-old woman with a known history of metastatic haemangiopericytoma presented with intractable hypoglycaemia. Hypoglycaemia was accompanied by undetectable serum insulin levels with high levels of proforms of insulin-like growth factor-II (‘big’ IGF-II). Reduction of tumour load with embolisation resulted in a normal pattern of serum glucose levels throughout the day. 2002 Published by Elsevier Science B.V. Keywords: Haemangiopericytoma; Hypoglycaemia; Embolisation
1. Introduction Haemangiopericytoma is a rare soft-tissue sarcoma, originating from pericapillary pericytes, which occasionally causes hypoglycaemia associated with a highly expressed insulin-like growth factor-II (IGF-II) gene in tumour tissue [1]. Treatment of this disorder can be difficult and painstaking because of the massive tumour load mostly present at the time of presentation. We describe a patient with intractable hypoglycaemia associated with haemangiopericytoma who was successfully treated with tumour embolisation.
2. Case report A 48-year-old woman with metastatic haemangiopericytoma presented with repeated episodes of odd behaviour, especially early in the morning, which dis*Corresponding author. Tel.: 131-20-444-4319. E-mail address: [email protected] (K. Hoekman).
appeared after food intake. Ten years earlier, she had a craniotomy because of a haemangiopericytoma in the cerebellum. Six years later, she developed metastases in the right pelvis, which were treated with radiotherapy. A year later, she received three cycles of ifosfamide and doxorubicin, followed by peripheral stem cell transplantation because of liver metastasis. A minor anti-tumour response was observed. Physical examination at admission showed an enlarged liver. Computer tomography (CT) scan showed a large hepatic and pelvic metastasis (Fig. 1). Her serum glucose level after a 1-h fast was 1.6 mmol / l and was accompanied by an undetectable insulin and c-peptide level. Hypoglycaemia was further associated with low levels of growth hormone, glucagon, catecholamines and cortisol, suggesting that normal counter-regulatory responses to hypoglycaemia were suppressed. Non-islet cell tumour-induced hypoglycaemia (NICTH) was suspected. Hypoglycaemic episodes were initially treated with dietary measures and thereafter with somatostatin without success. Surgical removal was not possible due to the size of the tumour. Embolisation of the liver and pelvic metastasis with ‘contour particles’ (Target Thera-
0953-6205 / 02 / $ – see front matter 2002 Published by Elsevier Science B.V. PII: S0953-6205( 02 )00087-0
P.W.B. Nanayakkara et al. / European Journal of Internal Medicine 13 (2002) 340 – 343
Fig. 1. A large (a) hepatic and (b) pelvic metastasis from a haemangiopericytoma.
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P.W.B. Nanayakkara et al. / European Journal of Internal Medicine 13 (2002) 340 – 343
peutics, Boston, USA) was performed to reduce the tumour load. This resulted in a normal pattern of serum glucose levels throughout the day.
3. Discussion For some time it has been recognised that the insulinlike growth factor (IGF) family is responsible for hypoglycaemia associated with haemangiopericytoma. IGF-I is the mediator of many of the effects of growth hormone, whereas IGF-II has no well-defined function in adult life. IGF-II is produced by many tissues and cell types. It is synthesised as a propeptide with a 89-aminoacid carboxyl extension, commonly called the E-domain (IGF-IIE), which is subsequently processed to mature 67 amino acid containing 7.4 kDa IGF-II [2]. In subjects with tumour hypoglycaemia, it has been reported that as much as 80% of IGF-II may circulate as biologically active proforms of IGF-II with a molecular mass of up to 15 kDa (‘big’ IGF-II). This heterogeneous big IGF-II contains partially processed E-peptide and is biologically active through stimulation of IGF-I and insulin receptors. Although bigIGF-II is elevated in most patients with tumour induced hypoglycaemia, this alone would be insufficient to explain hypoglycaemia if its bioavailability is not controlled by IGF binding proteins (IGFBPs). Six different types of IGFBPs have been described. Based on gel filtration experiments, one can distinguish two major pools of IGF– IGFBP complexes in the circulation. One is a heterotrimeric 150-kDa complex consisting of IGF, IGFBP-3 and an additional acid-labile subunit (ALS), which normally contains more than 80% of the total amount of IGFs in plasma. The capillary barrier limits the bioavailability of this relatively large complex. Both IGFBP-3 and ALS are GH-dependent. The other is a smaller 50–60 kDa pool consisting of binary IGF–IGFBP-3 complexes and IGFs complexed to other IGFBPs, which bind up to 20% of the IGFs. These complexes more readily cross the capillary barrier and interact with insulin receptors in the liver, muscle and adipocytes [3]. Less than 1% of the IGFs remains unbound. In tumour-induced hypoglycaemia, the content of 150 kDa complex is decreased whereas that of 50–60 kDa complex and of unbound IGF-II fraction are
substantially increased. This probably results from the impaired ability of big IGF-II to form ternary complexes. The incompletely processed IGF-II is able to bind to IGF-I receptors in the pituitary gland and pancreas, leading to suppression of growth hormone and insulin secretion. The apparent GH-deficient state subsequently reduces plasma ALS, IGF-I and IGFBP-3, resulting in a further reduction of 150 kDa complex formation. In the present case, before embolisation, an excessive amount of IGF-IIE and IGFBP-6, which has a preferential affinity for IGF-II [4], was found in the patient’s plasma (Table 1). The concentrations of IGF-I and IGFBP-3 were low. The extent of ternary 150 kDa complex formation in the circulation was studied by incubating [ 125 I]-IGF-II tracer with either the patient’s or normal control plasma, followed by neutral gel filtration through a Hiload S200 column. Using this procedure it was found that, compared to the normal situation, the capacity of 150 kDa complex formation in the patient’s plasma was significantly reduced (by about 40%) and a substantial proportion (|24%) of the [ 125 I]-IGF-II remained in the free form. Tumour embolisation led to a rapid decrease in IGF-IIE and IGFBP-6 levels (Table 1) and immediate restoration of normal glucose patterns. Two weeks after embolisation, the distribution of [ 125 I]-IGF-II binding complexes in the patient’s plasma was similar to that seen in normal plasma. However, IGF-I and IGFBP-3 levels in the circulation did not normalise, indicating that the GH–IGF-I axis had not fully recovered. Treatment of NITCH can often be painstaking and difficult because of the massive tumour load and severity of the symptoms. When tumour load reduction with surgery or radiotherapy is not possible, other modalities, such as corticosteroid, growth hormone, glucagon or somatostatin administration, have been used with variable and limited success [5]. Corticosteroids may, in addition to their antihypoglycaemic action, also suppress IGF-II production by tumour tissue [6] and GH may reduce the IGF-II availability to tissues by increasing IGFBP-3 levels and acid labile subunit (ALS) and, thereby, increasing the ‘ternary complex’ formation [7]. We chose embolisation because of the many practical limitations of the abovementioned therapeutic options, such as the necessity of frequent administration, side effects and high cost. With one session of embolisation we were able to keep the
Table 1 Plasma levels of IGFs and IGFBPs before and after embolisation of the tumour, as determined by specific radioimmunoassays (RIAs) Variable (nmol / l)
Before embolisation
1 day after embolisation
2 weeks after embolisation
Normative 2 S.D.-range values (n$15) for age and gender
IGF-I IGF-II IGF-IIE IGFBP-3 IGFBP-6
7.8 187.8 163.4 27.7 12.8
9.7 191.4 109.7 21.7 7.0
8.9 89.7 47.7 27.0 6.0
9.3–26.1 58.4–136.1 4.1–13.3 48.0–97.3 2.2–8.7
In the RIA for IGF-IIE, a polyclonal antibody, raised against a synthetic peptide containing the first 21 amino acids of the human IGF-II E-domain, was employed. A 9.7 kDa preparation of purified human pro-IGF-II served as a standard.
P.W.B. Nanayakkara et al. / European Journal of Internal Medicine 13 (2002) 340 – 343
patient symptom-free for 8 months; thereafter, we performed another embolisation with success. If and when the symptoms recur in the future, and if the embolisation is no longer possible, we can use the above-mentioned interventions as a last resort. We conclude that selective embolisation may successfully be used to alleviate symptoms caused by tumours with excessive production of hormones or growth factors.
References [1] Pavelic K, Spaventie S, Gluncic V et al. The expression and role of insulin-like growth factor II in malignant hemangiopericytomas. J Mol Med 1999;77:865–9. [2] Leroith D, Clemmons D, Nisseley P et al. Insulin-like growth factors
[3]
[4]
[5]
[6]
[7]
343
and non-islet-cell tumour hypoglycaemia. Metabolism 1993;42:1093–101. Chung J, Henry RR. Mechanisms of tumour-induced hypoglycaemia with intraabdominal haemangiopericytoma. J Clin Endocrinol Metab 1996;81:919–25. Hoekman K, van Doorn J, Gloudemans T et al. Hypoglycaemia associated with the production of IGF-II and IGFBP-6 by a hemangiopericytoma. Clin Endocrinol 1999;51(2):247–53. Gullo D, Sciacca L, Parrinello G et al. Treatment of haemangiopericytoma-induced hypoglycaemia with growth hormone and corticosteroids. J Clin Endocrinol Metab 1999;84:1758–9. Baxter RC, Holman SR, Corbould A et al. Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumour hypoglycemia. J Clin Endocrinol Metab 1995;80:2700–8. Teale JD, Blum WF, Marks V. Alleviation of non-islet cell tumours by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem 1992;29:314–23.
Brief report
Treatment of haemangiopericytoma-associated hypoglycaemia with embolisation P.W.B. Nanayakkara a , J. van Doorn b , F.G. van den Berg c , C.J. van Groeningen a , H.M. Pinedo a , a, K. Hoekman * a
Department of Medical Oncology, Vrije Universiteit Medische Centrum, Postbus 7075, 1007 MB Amsterdam, The Netherlands b Laboratory of Endocrinology, Wilhelmina Children’ s Hospital, University Medical Centre, Utrecht, The Netherlands c Department of Radiology, Vrije Universiteit Medische Centrum, Amsterdam, The Netherlands Received 13 August 2001; received in revised form 21 January 2002; accepted 4 April 2002
Abstract A 48-year-old woman with a known history of metastatic haemangiopericytoma presented with intractable hypoglycaemia. Hypoglycaemia was accompanied by undetectable serum insulin levels with high levels of proforms of insulin-like growth factor-II (‘big’ IGF-II). Reduction of tumour load with embolisation resulted in a normal pattern of serum glucose levels throughout the day. 2002 Published by Elsevier Science B.V. Keywords: Haemangiopericytoma; Hypoglycaemia; Embolisation
1. Introduction Haemangiopericytoma is a rare soft-tissue sarcoma, originating from pericapillary pericytes, which occasionally causes hypoglycaemia associated with a highly expressed insulin-like growth factor-II (IGF-II) gene in tumour tissue [1]. Treatment of this disorder can be difficult and painstaking because of the massive tumour load mostly present at the time of presentation. We describe a patient with intractable hypoglycaemia associated with haemangiopericytoma who was successfully treated with tumour embolisation.
2. Case report A 48-year-old woman with metastatic haemangiopericytoma presented with repeated episodes of odd behaviour, especially early in the morning, which dis*Corresponding author. Tel.: 131-20-444-4319. E-mail address: [email protected] (K. Hoekman).
appeared after food intake. Ten years earlier, she had a craniotomy because of a haemangiopericytoma in the cerebellum. Six years later, she developed metastases in the right pelvis, which were treated with radiotherapy. A year later, she received three cycles of ifosfamide and doxorubicin, followed by peripheral stem cell transplantation because of liver metastasis. A minor anti-tumour response was observed. Physical examination at admission showed an enlarged liver. Computer tomography (CT) scan showed a large hepatic and pelvic metastasis (Fig. 1). Her serum glucose level after a 1-h fast was 1.6 mmol / l and was accompanied by an undetectable insulin and c-peptide level. Hypoglycaemia was further associated with low levels of growth hormone, glucagon, catecholamines and cortisol, suggesting that normal counter-regulatory responses to hypoglycaemia were suppressed. Non-islet cell tumour-induced hypoglycaemia (NICTH) was suspected. Hypoglycaemic episodes were initially treated with dietary measures and thereafter with somatostatin without success. Surgical removal was not possible due to the size of the tumour. Embolisation of the liver and pelvic metastasis with ‘contour particles’ (Target Thera-
0953-6205 / 02 / $ – see front matter 2002 Published by Elsevier Science B.V. PII: S0953-6205( 02 )00087-0
P.W.B. Nanayakkara et al. / European Journal of Internal Medicine 13 (2002) 340 – 343
Fig. 1. A large (a) hepatic and (b) pelvic metastasis from a haemangiopericytoma.
341
342
P.W.B. Nanayakkara et al. / European Journal of Internal Medicine 13 (2002) 340 – 343
peutics, Boston, USA) was performed to reduce the tumour load. This resulted in a normal pattern of serum glucose levels throughout the day.
3. Discussion For some time it has been recognised that the insulinlike growth factor (IGF) family is responsible for hypoglycaemia associated with haemangiopericytoma. IGF-I is the mediator of many of the effects of growth hormone, whereas IGF-II has no well-defined function in adult life. IGF-II is produced by many tissues and cell types. It is synthesised as a propeptide with a 89-aminoacid carboxyl extension, commonly called the E-domain (IGF-IIE), which is subsequently processed to mature 67 amino acid containing 7.4 kDa IGF-II [2]. In subjects with tumour hypoglycaemia, it has been reported that as much as 80% of IGF-II may circulate as biologically active proforms of IGF-II with a molecular mass of up to 15 kDa (‘big’ IGF-II). This heterogeneous big IGF-II contains partially processed E-peptide and is biologically active through stimulation of IGF-I and insulin receptors. Although bigIGF-II is elevated in most patients with tumour induced hypoglycaemia, this alone would be insufficient to explain hypoglycaemia if its bioavailability is not controlled by IGF binding proteins (IGFBPs). Six different types of IGFBPs have been described. Based on gel filtration experiments, one can distinguish two major pools of IGF– IGFBP complexes in the circulation. One is a heterotrimeric 150-kDa complex consisting of IGF, IGFBP-3 and an additional acid-labile subunit (ALS), which normally contains more than 80% of the total amount of IGFs in plasma. The capillary barrier limits the bioavailability of this relatively large complex. Both IGFBP-3 and ALS are GH-dependent. The other is a smaller 50–60 kDa pool consisting of binary IGF–IGFBP-3 complexes and IGFs complexed to other IGFBPs, which bind up to 20% of the IGFs. These complexes more readily cross the capillary barrier and interact with insulin receptors in the liver, muscle and adipocytes [3]. Less than 1% of the IGFs remains unbound. In tumour-induced hypoglycaemia, the content of 150 kDa complex is decreased whereas that of 50–60 kDa complex and of unbound IGF-II fraction are
substantially increased. This probably results from the impaired ability of big IGF-II to form ternary complexes. The incompletely processed IGF-II is able to bind to IGF-I receptors in the pituitary gland and pancreas, leading to suppression of growth hormone and insulin secretion. The apparent GH-deficient state subsequently reduces plasma ALS, IGF-I and IGFBP-3, resulting in a further reduction of 150 kDa complex formation. In the present case, before embolisation, an excessive amount of IGF-IIE and IGFBP-6, which has a preferential affinity for IGF-II [4], was found in the patient’s plasma (Table 1). The concentrations of IGF-I and IGFBP-3 were low. The extent of ternary 150 kDa complex formation in the circulation was studied by incubating [ 125 I]-IGF-II tracer with either the patient’s or normal control plasma, followed by neutral gel filtration through a Hiload S200 column. Using this procedure it was found that, compared to the normal situation, the capacity of 150 kDa complex formation in the patient’s plasma was significantly reduced (by about 40%) and a substantial proportion (|24%) of the [ 125 I]-IGF-II remained in the free form. Tumour embolisation led to a rapid decrease in IGF-IIE and IGFBP-6 levels (Table 1) and immediate restoration of normal glucose patterns. Two weeks after embolisation, the distribution of [ 125 I]-IGF-II binding complexes in the patient’s plasma was similar to that seen in normal plasma. However, IGF-I and IGFBP-3 levels in the circulation did not normalise, indicating that the GH–IGF-I axis had not fully recovered. Treatment of NITCH can often be painstaking and difficult because of the massive tumour load and severity of the symptoms. When tumour load reduction with surgery or radiotherapy is not possible, other modalities, such as corticosteroid, growth hormone, glucagon or somatostatin administration, have been used with variable and limited success [5]. Corticosteroids may, in addition to their antihypoglycaemic action, also suppress IGF-II production by tumour tissue [6] and GH may reduce the IGF-II availability to tissues by increasing IGFBP-3 levels and acid labile subunit (ALS) and, thereby, increasing the ‘ternary complex’ formation [7]. We chose embolisation because of the many practical limitations of the abovementioned therapeutic options, such as the necessity of frequent administration, side effects and high cost. With one session of embolisation we were able to keep the
Table 1 Plasma levels of IGFs and IGFBPs before and after embolisation of the tumour, as determined by specific radioimmunoassays (RIAs) Variable (nmol / l)
Before embolisation
1 day after embolisation
2 weeks after embolisation
Normative 2 S.D.-range values (n$15) for age and gender
IGF-I IGF-II IGF-IIE IGFBP-3 IGFBP-6
7.8 187.8 163.4 27.7 12.8
9.7 191.4 109.7 21.7 7.0
8.9 89.7 47.7 27.0 6.0
9.3–26.1 58.4–136.1 4.1–13.3 48.0–97.3 2.2–8.7
In the RIA for IGF-IIE, a polyclonal antibody, raised against a synthetic peptide containing the first 21 amino acids of the human IGF-II E-domain, was employed. A 9.7 kDa preparation of purified human pro-IGF-II served as a standard.
P.W.B. Nanayakkara et al. / European Journal of Internal Medicine 13 (2002) 340 – 343
patient symptom-free for 8 months; thereafter, we performed another embolisation with success. If and when the symptoms recur in the future, and if the embolisation is no longer possible, we can use the above-mentioned interventions as a last resort. We conclude that selective embolisation may successfully be used to alleviate symptoms caused by tumours with excessive production of hormones or growth factors.
References [1] Pavelic K, Spaventie S, Gluncic V et al. The expression and role of insulin-like growth factor II in malignant hemangiopericytomas. J Mol Med 1999;77:865–9. [2] Leroith D, Clemmons D, Nisseley P et al. Insulin-like growth factors
[3]
[4]
[5]
[6]
[7]
343
and non-islet-cell tumour hypoglycaemia. Metabolism 1993;42:1093–101. Chung J, Henry RR. Mechanisms of tumour-induced hypoglycaemia with intraabdominal haemangiopericytoma. J Clin Endocrinol Metab 1996;81:919–25. Hoekman K, van Doorn J, Gloudemans T et al. Hypoglycaemia associated with the production of IGF-II and IGFBP-6 by a hemangiopericytoma. Clin Endocrinol 1999;51(2):247–53. Gullo D, Sciacca L, Parrinello G et al. Treatment of haemangiopericytoma-induced hypoglycaemia with growth hormone and corticosteroids. J Clin Endocrinol Metab 1999;84:1758–9. Baxter RC, Holman SR, Corbould A et al. Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumour hypoglycemia. J Clin Endocrinol Metab 1995;80:2700–8. Teale JD, Blum WF, Marks V. Alleviation of non-islet cell tumours by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem 1992;29:314–23.