A 51-year-old woman affected by advanced aggressive fibromatosis of the abdomen was admitted to the hospital because of diabetes associated with severe insulin resistance. Her medical history was notable for 1) desmoid tumor of the abdomen at age 26 years, which had undergone 32 surgical resections (according to the patient), until the age of 44 and 2) diabetes at age 45 years initially treated with oral agents and then by insulin, with persistent poor glucose control despite progressively increasing doses. Afterward, the patient received an intravenous insulin infusion by an external pump through a port-a-cath in the subclavian vein for severe insulin resistance. Intravenous insulin was discontinued due to sepsis, which resolved after intravenous antibiotic therapy. Family history was negative for diabetes. Physical examination revealed poor general conditions and a large mesogastric lesion (Fig. 1A), and BMI was 29.2 kg/m2 and blood pressure was 140/80 mmHg. Laboratory investigations were normal, apart from features of nonketotic insulin-resistant diabetes with HbA1c 14.2%, 24-h blood glucose 300–500 mg/dl, fasting insulin 144 μU/ml, proinsulin 45 pmol/l, and C-peptide 2.88 ng/ml. Autoantibodies to insulin receptor and insulin were absent, and tumor necrosis factor-α (12.5 pg/ml) and interleukin-6 (11.6 pg/ml) were elevated. Intravenous insulin (1,200 units/day) had to be resumed. The extreme insulin resistance in the absence of insulin receptor antibodies was suggestive of a paraneoplastic origin. Surgical intervention was unfeasible due to tumor diffusion and impossibility to reconstruct the abdominal wall. Immunocytochemistry on the desmoid tumor biopsies revealed the presence of α- and β-platelet–derived growth factor (PDGF) receptors.
In view of the impracticability of maintaining long-term intravenous insulin, therapy with imatinib mesylate (Gleevec) was considered (1–3). After obtaining ethical committee permission and patient’s informed consent, imatinib was started at the dose of 400 mg/day orally. Insulin requirement dropped dramatically to 500 units/day s.c. within 3 days and then progressively to a nadir of 100 units/day after 2 months, accompanied by a significant decrease of tumor mass and improvement of general clinical conditions and diabetes control. After 6 months of treatment with imatinib and while still on treatment with it, partial reenlargement of the lesion and insulin resistance slowly recurred with insulin requirement increasing up to 600 units/day after 8 months of imatinib treatment (Fig. 1B–G). At that point, leukopenia and anemia occurred and imatinib had to be discontinued for this reason, with further worsening of severe insulin-resistant diabetes.
We hypothesize that imatinib acted positively by blocking the negative intracellular cross-talk between PDGF, tumor necrosis factor-α, interleukin-6, and insulin, either by a direct inhibition of the PDGF tyrosine kinase or by reducing the tumor mass and the related production of interleukin-6, tumor necrosis factor-α, and PDGF (3–5).
The clinical and metabolic response of the patient to imatinib therapy. A: The desmoid tumor is a large mesogastric easily bleeding lesion. B–F: The lesion was measured at admission and after 2, 4, 6, and 8 months of imatinib therapy, demonstrating progressive reduction in the external size of the tumor with a partial recurrence at 8 months. Daily insulin requirements (G) and HbA1c levels (H) demonstrate a clear-cut positive effect of the therapy with the tyrosine kinase inhibitor.
The clinical and metabolic response of the patient to imatinib therapy. A: The desmoid tumor is a large mesogastric easily bleeding lesion. B–F: The lesion was measured at admission and after 2, 4, 6, and 8 months of imatinib therapy, demonstrating progressive reduction in the external size of the tumor with a partial recurrence at 8 months. Daily insulin requirements (G) and HbA1c levels (H) demonstrate a clear-cut positive effect of the therapy with the tyrosine kinase inhibitor.
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We gratefully acknowledge the generous gift by Dr. Raffaello Bertieri (Novartis, Milano, Italy) of Imatinib mesylate (Gleevec), used for the treatment of this patient.
