Synthesis and Secretion of Insulin-like Growth Factor II by a Leiomyosarcoma with Associated Hypoglycemia

Abstract

We describe a case of recurrent hypoglycemia apparently caused by secretion of insulin-like growth factor II (IGF-II) by a leiomyosarcoma. A 67-year-old woman presented with recurrent severe hypoglycemia and a large mass in the thorax. During hypoglycemia, plasma cortisol was elevated, but insulin and growth hormone levels were low. After resection of a large leiomyosarcoma, the hypoglycemia resolved. After an eight-year remission, both the tumor and symptomatic hypoglycemia recurred. During a second operation a second large tumor was removed, with relief of the patient's hypoglycemia. The tumor contained high concentrations of IGF-II mRNA and 2100 ng of IGF-II immunoreactive peptide per gram. Filtration through a BioGel P-60 gel column established that 77 percent of the IGF-II was present as a larger molecule, demonstrating incomplete processing of the pro-IGF-II peptides. A similar fraction of high-molecular-weight IGF-II was present in the serum, indicating that the tumor was the chief source of IGF-II. The high-molecular-weight IGF-II found in both the tumor and serum was fully reactive with the IGF-II receptor. Radioimmunoassay showed that the concentrations of insulin-like growth factor I (IGF-I) in tumor and serum were low, suggesting feedback inhibition of growth hormone secretion by IGF-II. Eight months after reoperation, plasma concentrations of IGF-I and IGF-II were normal, and high-molecular-weight IGF-II was virtually undetectable. We conclude that the most likely cause of this patient's recurrent hypoglycemia was IGF-II produced by the leiomyosarcoma.

Expression of insulin-like growth factor 2 in mesenchymal neoplasms

“…The majority of the circulating IGF2 in non-islet-cell tumor hypoglycemia is big IGF2, and circulating high levels in a case with leiomyosarcoma and in cases with GISTs were reduced after surgery. 13,21,23 The high expression of IGF2 protein in our study provides a biological explanation for case reports of GIST patients suffering from hypoglycemia. [18][19][20][21][22][23] This phenomenon has been observed relatively frequently in association with solitary fibrous tumor, in which associated hypoglycemia has been termed 'Doege-Potter Syndrome'.…”

“…Increased levels of circulating IGF2 (secretion from a tumor or reduced IGF2R receptor expression) can inhibit the secretion of growth hormone from the pituitary with secondarily decreased levels of IGF1 and insulin. 13,21 The prohomone form of IGF2, 'big IGF2', released from mesenchymal tumors interacts poorly with IGF-binding proteins, thereby disproportionately increasing the level of unbound IGF, and has been reported to have a higher affinity for the insulin receptor than physiological IGF2. 13 Severe hypoglycemia has been associated with non-islet-cell tumors and IGF2 is known to have such hypoglycemic effects presumably through insulin-like activity.…”

“…13,21 The prohomone form of IGF2, 'big IGF2', released from mesenchymal tumors interacts poorly with IGF-binding proteins, thereby disproportionately increasing the level of unbound IGF, and has been reported to have a higher affinity for the insulin receptor than physiological IGF2. 13 Severe hypoglycemia has been associated with non-islet-cell tumors and IGF2 is known to have such hypoglycemic effects presumably through insulin-like activity. The majority of the circulating IGF2 in non-islet-cell tumor hypoglycemia is big IGF2, and circulating high levels in a case with leiomyosarcoma and in cases with GISTs were reduced after surgery.…”

“…[10][11][12] Some mesenchymal (non-islet cell) tumors produce and release an excessive amount of a prohormone form of IGF2 (often termed, 'big IGF2'). 13 Clues about which tumor types are most likely to be dependent on IGF signaling can come from gene expression profiling studies. Publicly available datasets show consistently that IGF2 is very highly expressed in gastrointestinal stromal tumors (GISTs), indeed making it one of the strongest discriminators for this diagnosis.…”

Clinical implications of serum C‐reactive protein levels in malignant fibrous histiocytoma

“…1,2 However, PNSs in other soft tissue sarcomas, including other subtypes of MFH, are rarely reported and the frequency remains unknown. [13][14][15] Here, we have determined that PNS with elevated serum CRP levels frequently occurs in MFH patients (65%, 30/46), particularly in those with pleomorphic-storiform type (93%, 28/30); our series did not include inflammatory MFH.…”