Invasive Giant Prolactinoma with Loss of Therapeutic Response to Cabergoline: Expression of Angiogenic Markers

Mallea-Gil, María Susana; Cristina, Carolina; Millán, María Inés Pérez; Villafañe, Ana M. Rodriguez; Ballarino, Carolina; Stalldecker, Graciela; Becú-Villalobos, Damasia

doi:10.1007/s12022-009-9057-3

Cited by 27 publications

(18 citation statements)

References 36 publications

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“…Only six such patients have been reported in the literature (excluding malignant transformation) (3,4,5,6,7). The possible explanations for acquired non-responsiveness include non-compliance, onset of gonadal steroid replacement that causes dopamine resistance in the lactotrophs, and, rarely, transformation to carcinoma (37,41).…”

Section: Discussionmentioning

confidence: 99%

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Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

Shimazu

Shimatsu

Yamada

et al. 2012

European Journal of Endocrinology

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Objective: Dopamine agonists normalize prolactin (PRL) levels and reduce tumour size in responsive prolactinoma. However, several cases have shown resistance to dopamine agonists upon initial treatment. Infrequently, prolactinoma initially responds, but then becomes refractory to prolonged treatment (secondary resistance). We investigated the possible mechanisms of resistance to dopamine agonists. Subjects and methods: Twelve cases of prolactinoma were surgically resected and classified according to the responsiveness of PRL levels and tumour size to dopamine agonists: good responders (nZ5), poor responders (nZ5), or secondary resistance (nZ2). We examined the expression of dopamine D 2 receptor (D 2 R) isoform (short: D 2 S and long: D 2 L) mRNA and protein. We investigated DNA methylation patterns in the promoter region of the DRD2 gene. Results: The predominant D 2 R isoform expressed in prolactinoma was D 2 L. Levels of D 2 L mRNA were significantly lower in secondary resistance and poor responders than in good responders. Expression of D 2 R protein was variable among cases. Almost no CpG sites of the DRD2 gene promoter region were methylated. Conclusion: Resistance of prolactinoma to dopamine agonists is correlated with a reduction in D 2 L isoform mRNA levels. Silencing of the DRD2 gene by methylation in the promoter region is unlikely to play a role in dopamine agonist resistance in prolactinoma.

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Section: Discussionmentioning

confidence: 99%

“…There have been very few reported cases of prolactinoma exhibiting secondary resistance, i.e. cases that show an initial response to dopamine agonists, but then become refractory with prolonged treatment (3,4,5,6,7).…”

Section: Introductionmentioning

confidence: 99%

Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

Shimazu

Shimatsu

Yamada

et al. 2012

European Journal of Endocrinology

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“…Orbital invasion is another rare extrasellar extension of pituitary tumours and will cause exophthalmos and optic nerve compression at the orbital apex (31,46,56). Finally, in the opposite direction, posterior and inferior extension may cause ataxia by cerebellar compression (57,58) or cranio-cervical junction instability (12,13,59). …”

Section: Presenting Featuresmentioning

confidence: 99%

“…Despite invasive features such as bone erosion and extension into surrounding CN structures, mitotic rates and immunohistochemistry for p53 and MIB-1 (Ki67) are often minimally increased (119). On the other hand, one single case study has demonstrated strong immunoreactivity for VEGF and FGF2 (two potent angiogenic factors) and for CD31 (an endothelial marker) in a giant invasive macroprolactinoma, thus suggesting high tumoural vascularization (57). Identification of new molecular markers highly expressed or down-regulated in these giant tumours should help to better understand their origin and progression (27,120) and to find new therapeutic modalities, such as drugs interfering with angiogenesis or cell proliferation.…”

Section: Perspectives In the Management Of Giant Prolactinomasmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

Maiter

Delgrange

2014

European Journal of Endocrinology

160

166

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Giant prolactinomas are rare tumours, representing only 2-3% of all prolactin (PRL)-secreting tumours and raising special diagnostic and therapeutic challenges. Based on several considerations developed in this review, their definition should be restricted to pituitary adenomas with a diameter of 40 mm or more, significant extrasellar extension, very high PRL concentrations (usually above 1000 mg/l) and no concomitant GH or ACTH secretion. Giant prolactinomas are much more frequent in young to middle-aged men than in women, with a male to female ratio of about 9:1. Endocrine symptoms are often present but overlooked for a long period of time, and diagnosis is eventually made when neurologic complications arise from massive extension into the surrounding structures, leading to cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos. PRL concentrations are usually in the range of 1000-100 000 mg/l, but may be underestimated by the so-called 'high-dose hook effect'. As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction in tumour size in three-fourths of the patients and PRL normalization in 60-70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment) or to patients with insufficient tumoural response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours, which are not controlled despite combined medical and surgical treatments. Because of these various challenges, we advocate a multidisciplinary management of these giant tumours in expert centres.

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“…There are only two reports reporting VEGF expression pituitary adenomas using Western blot, one in which a small selection of human pituitary adenomas were evaluated [15] and a second one performed in 24 adenomas, most of which were nonfunctioning [16]. As VEGF immunostaining is highly heterogeneous between adenoma samples [17] and MVD evaluation using immunohistochemistry has some limitations, we wished to study the expression of VEGF and CD31 measured by Western blot in a series of pituitary adenomas in order to add to the comprehension of angiogenic markers in these tumors.…”

Section: Introductionmentioning

confidence: 99%

VEGF and CD31 Association in Pituitary Adenomas

et al. 2010

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Pituitary tumors are usually less vascularized than the normal pituitary, and the role of angiogenesis in these adenomas is contentious. Appraisal of microvascular density and expression of the potent angiogenic vascular endothelial growth factor (VEGF) by immunohistochemistry has yielded controversial results, as a broad spectrum of immunostaining can be found. We determined the protein expression of VEGF and CD31, an endothelial marker, in a series of 56 surgically removed pituitary adenomas using Western blot assay. Prolactinomas had higher VEGF protein expression compared to nonfunctioning or ACTH- and GH-secreting adenomas, while CD31 was similar in the different adenoma histotypes. VEGF and CD31 were not affected by sex, age, years of adenoma evolution, or proliferation rate (Ki67 and PCNA) for all adenoma types. Only in nonfunctioning adenomas CD31 concentration increased significantly with age. There was a positive correlation between CD31 and VEGF expression when all adenoma histotypes were considered, or when prolactinomas and nonfunctioning adenomas were evaluated separately. The positive association of VEGF and CD31 expression suggests the participation of angiogenesis in adenoma development, while epithelial cell proliferation in pituitary tumors is not directly related to VEGF or CD31 expression, and other factors, such as primary genetic alterations may be involved.

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Invasive Giant Prolactinoma with Loss of Therapeutic Response to Cabergoline: Expression of Angiogenic Markers

Cited by 27 publications

References 36 publications

Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

VEGF and CD31 Association in Pituitary Adenomas

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