A 41-year-old man with clinically evident acromegaly was referred to our department on his own initiative due to the physical changes over the years that had been noticed by the new wife by looking at past pictures. He stated that 1 year before had undergone surgery for carpal tunnel syndrome and for some months he reported snoring, profuse sweating, joint aches and occasional headache. He denied to have hypertension, galactorrhea, signs and symptoms of diabetes mellitus.
At clinical examination, the patient showed a clear acromegalic phenotype, with prominence of the brow, enlargement of the nose, thickening of the lips, prognathism, macroglossia, increased interdental spacing, acral enlargement, evident thyroid goiter. He showed blood pressure values into normal range, normal cardiac and respiratory exam, a mild splenomegaly.
Initial testing revealed IGF-1 1369 μg/l (normal: 109-204), basal-GH 31 μg/l with GH-nadir during an oral glucose tolerance test (OGTT) 16 μg/l, prolactin 2386 ng/ml (normal: < 15.2 ng/ml), total testosterone 0.88 μg/l (normal: 2.4-9.3 μg/l) with normal gonadotropins, parathyroid hormone 52 pg/ml (normal: 15-65 pg/ml), normal adrenal and thyroid function. The patient showed normal glucose tolerance (fasting glucose 4.78 mmol/l), with mild hyperinsulinism (OGTT-peak 230.6 μU/ml), glycosylate hemoglobin (HbA1c) 5.9%) and normal lipid profile. Magnetic resonance imaging (MRI) revealed a large hyperintense mass of 28,512 mm3 (largest diameter 33 mm) with supra- and latero-sellar extension (with bilateral, mostly left, involvement of the cavernous sinus). Campimetry showed monolateral inferior quadrantanopsia.
The patient refused surgery as a first line treatment and started treatment with cabergoline (0.5-1.0 mg/weekly) and lanreotide-autogel 90 mg/monthly.
After 3 and 6 months he showed, respectively, IGF-1 1049-908 μg/l, basal-GH 35.6-44 μg/l; prolactin 1526-959 ng/ml. No side effects were reported, except for a quite significant increase in fasting glucose (6.44 mmol/l) and HbA1c (6.5%). At 6 months MRI revealed a volumetric tumor reduction (23,500 mm3) with depression of the superior profile. Treatment was modified by increasing cabergoline to 1.5 mg/weekly and lanreotide to 120 mg/monthly for 6 months. A further, very small, decrease in hormonal levels was obtained, but without reaching the target, as follows: IGF-1850 μg/l, basal-GH 32 μg/l, prolactin 589 ng/ml. MRI showed an almost unchanged tumor mass. Fasting glucose (6.22 mmol/l) and HbA1c (6.5%) did not significantly change.
The patient was persuaded to undergo transsphenoidal adenomectomy, without complications, in july 2012. Histologically, the tumor was classified as GH/PRL and sparsely-granulated type, with a Ki-67 labeling index < 1%.
Despite a significant debulking of tumor, surgery was not curative but it probably led to a better biochemical response to subsequent medical treatment. The early random-GH after 1 month was 47 μg/L and the evaluation at 3 months confirmed persistent disease, with IGF-1631 μg/l, random-GH 15.2 μg/L, nadir-GH 11.5 μg/L. PRL was 251.9 ng/ml, total testosterone slightly increased (1.85 μg/l) and glucose metabolism back in the norm (fasting glucose 5.17 mmol/l, HbA1c 6.0%, insulin OGTT-peak 132.6 μU/ml). MRI revealed a residual tumor with left extension and campimetry was normal.
The patient started adjuvant therapy with octreotide-LAR and cabergoline, with the dosage progressively increased (maximum doses octreotide 40 mg/monthly and cabergoline 2.25 mg/weekly). This treatment did not result in hormonal normalization, as shown by random-GH 10.9 μg/L, IGF-1549 μg/l, PRL 76 ng/ml.
In august 2013 PEG was added to octreotide with a 3-times-a-week schedule as follows: 60 mg/weekly for 4 months, 90 mg/weekly for other 4 months and 120 mg/weekly for just 3 months (cabergoline dose unchanged). A dose-responsive IGF-1 reduction (437, 410 and 305 μg/l, respectively) was observed as the PEG dose gradually increased, although IGF-1 and PRL (72 ng/ml) remained above the norm. No significant change in tumor volume was seen and the glucose metabolism slightly improved (last HbA1c 5.8%). However, PEG was stopped by the patient due to lack of clinical improvement and poor compliance of patient to PEG treatment in the following weeks.
In july 2014, as there was still no commercial use of pasireotide, we had the opportunity to use it as compassionate treatment. We replaced octreotide with pasireotide-LAR 40 mg/monthly (cabergoline dose unchanged). After 6 months random-GH was 12.07 μg/L, IGF-1613 μg/L and PRL 41.2 ng/ml, with increased fasting glucose (6.17 mmol/l) and HbA1c (6.4%). MRI showed a decrease in tumor volume (15,525 mm3) and a heterogeneous signal intensity, with predominant hyperintensity, on both T1 and T2-weighted images compatible with presence of necrotic areas.
Pasireotide was increased to 60 mg/monthly for 4 months without significant biochemical benefits: random-GH 10.9 μg/L, IGF-1518.9 μg/L.
In june 2015, after obtaining informed consent from the patient who refused surgery, PEG was added to pasireotide with a 6-times-a-week schedule, with a starting daily dose of 10 mg (60 mg/weekly), gradually increased to 15 (90 mg/weekly) up to 20 mg (120 mg/weekly) after 3 and 6 months (cabergoline dose unchanged). After 3 months of PEG-10 mg, 3 months of PEG-15 mg and 6 months of PEG-20 mg, IGF-1 was 344-234-172 μg/L and PRL 30-28.5-19 ng/ml, respectively. Fasting glucose was 6.5-5.06-5.39 mmol/l, while HbA1c changed from 6.4 to 6.8-5.9-5.5%. After 12 months, MRI revealed an unchanged tumor volume. Clinically, an improvement in tiredness and joint pain was reported. The patient’s compliance was satisfactory throughout the whole period of treatment and no side effects were reported. To date, the patient is continuing the treatment with the latest available IGF-1174 μg/L and PRL 9.5 ng/ml.
IGF-1 and fasting glucose levels during the entire clinical follow-up of the patient are presented in the Fig. 1.
MR coronal images at diagnosis and during the follow-up of the patient are presented in the Fig. 2.