LOSS OF THERAPEUTIC RESPONSE TO CABERGOLINE IN AN INVASIVE GIANT PROLACTINOMA

M.C.BALLARINO; M.C.RIDRUEJO; K.BERTINI; M.M.APARICIO; A.RODRIGUEZ V; M.AMAOLO; S.PALLINI; V. PASSANTE; C.CRISTINA; D.BECU-VILLALOBOS; M.S.MALLEA GIL

Athens Greece

Congreso; 12th Meeting of the European Neuroendocrine Associaton, ENEA; 2006

European Neuroendocrine Associaton

 A 70 –year- old Caucasian man was referred for evaluation of a giant sellar-extrasellar mass with extension in the right temporal lobe, tumor volume: 202 cc.. He suffered from  frontal headache,  sleep and saciety disorder.  He had a history of hypothyroidism and consequent  hyperthyroidism treatment with methimazole and was medicated with levothyroxine. Physical examination:  pulse: 80 bpm, blood pressure: 120-80 mmHg, attention deficit was observed. Unsteady gait with tendency to veer to the left.       Initial laboratory findings: Prolactin : 8.800 ng/ml (N: 2.6-13.1),  low LH, FSH and Testosterone, normal cortisol. Visual Field:. could not be achieved because of lack of cooperation. With diagnosis of invasive giant prolactinoma, we prescribed  cabergoline at increasing doses, max: 5mg/day. Three years later, the patient presented an overall improvement, reduction in adenoma volume by 94.2 % and  Prolactin level: 35.8 ng/ml. Subsequently, there was a progressive  increase in  the  tumor volume and  Prolactin level, returning to the initial stage. IGF1 measurement  was performed yielding a frankly elevated value of 974 ng/ml (N: 70-360). Given the size of the tumor, visual symptoms, elevated IGF 1 and unresponding prolactin levels, surgery was decided. Partial resection was performed via transcranial approach. Pathology reports: Immunochemistry: positive prolactin.  GH staining using confocal microscopy revealed scattered positivity in adenoma cells. Tumor was positive for CD31 in endothelial cells, and VEGF-A (a potent growth factor involved in tumor angiogenesis) immunoreactivity was found both in endothelial and in tumor cells.  Immunostaining could be detected in cytoplasm and in some nuclei. Discussion: This patient obtained good response to 5 mg/day cabergoline in the first three years of treatment, but then there was an increase in tumor volume and prolactin levels suggesting  there had been a change in tumor behavior and a possible resistance. Elevated IGF1 was found with absence of acromegalic features. Pathology results after tumor resection revealed a mixed tumor, which was positive for both prolactin and GH. GH results were similar to those described in  “poorly functioning somatotroph tumors” in which patients do not present acromegalic features, and have scattered and weak immunoreactivity for GH. In these tumors suprasellar extension or cavernous sinus invasion seems to be a common feature 1. As in an experimental study we demonstrated that VEGF-A is increased in resistant prolactinomas 2, and in humans VEGF-A is increased in adenomas 3  4 we studied VEGF-A expression in this tumor. We found that  VEGF-A was expressed in endothelial cells as well as in tumor cells. The expression of both CD31 and VEGF-A  indicated that the tumor was highly vascularized. We conclude that the prolactinoma evolved to resistency, and we speculate that significant excess of GH was a relatively new occurrence in this patient, either because tumor cells started secreting GH late, or because the tumor was so inefficient in producing GH that a very large tumor burden was required to cause biochemical evidence of excess GH. This is in accordance with the lack of acromegalic features in the patient. Furthermore the tumor was highly vascularized and expressed VEGF-A. Reference List          1. A. Sidhaye, P. Burger, D. Rigamonti, R. Salvatori, Neurosurgery 56, E1154 (2005).          2. C. Cristina et al., Endocrinology. 146, 2952-2962 (2005).          3. M. Niveiro, F. I. Aranda, G. Peiro, C. Alenda, A. Pico, Hum.Pathol. 36, 1090-1095 (2005).          4. M. Fedele et al., Oncogene 21, 3190-3198 (2002).