Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly

Fougner, Stine Lyngvi; Casar‐Borota, Olivera; Heck, Ansgar; Berg, Jens Petter; Bollerslev, Jens

doi:10.1111/j.1365-2265.2011.04163.x

Cited by 181 publications

(125 citation statements)

References 33 publications

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“…However, while mutation of PRKACA appears to be important for the development of up to two-thirds of cortisol-producing adrenal adenomas (9, 10), it does not appear to be the case for somatotroph adenomas, even though mutation of the cAMP signalling pathway has been shown to be involved in the pathogenesis of this tumour type (1, 2,13,14,15,16,17,18,19). We did not determine whether there was amplification of either the PRKACA or PRKACB gene in this series.…”

Section: Discussionmentioning

confidence: 63%

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas

Larkin

Ferraú

Karavitaki

et al. 2014

European Journal of Endocrinology

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Objective: The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas. Design: Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study. Methods: The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern. Results: No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns. Conclusions: It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.

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Section: Discussionmentioning

confidence: 63%

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas

Larkin

Ferraú

Karavitaki

et al. 2014

European Journal of Endocrinology

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“…This is in agreement with the recent findings of Fougner et al, who in their recent analysis of 78 tumors concluded that densely granulated tumors produce more IGF-1 per unit of tumor volume than do sparsely granulated tumors. 5 They noted a similar trend for GH, although it did not reach significance. Obari et al had previously noted higher mean plasma GH levels in patients with densely granulated and mixed tumors compared with patients with sparsely granulated tumors, and Bakhtiar et al had previously found that the GH-producing index (peripheral GH levels per cubic centimeter of tumor) was lower in sparsely granulated compared with densely granulated tumors.…”

Section: Discussionmentioning

confidence: 71%

Percent reduction of growth hormone levels correlates closely with percent resected tumor volume in acromegaly

Schwyzer¹,

Starke²,

Jane³

et al. 2015

JNS

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OBJECT Correlation between tumor volume and hormone levels in individual patients would permit calculation of the fraction of tumor removed by surgery, by measuring postoperative hormone levels. The goals of this study were to examine the relationship between tumor volume, growth hormone (GH), and insulin-like growth factor–1 (IGF-1) levels, and to assess the correlation between percent tumor removal and the reduction in plasma GH and IGF-1 in patients with acromegaly. METHODS The 3D region of interest–based volumetric method was used to measure tumor volume via MRI before and after surgery in 11 patients with GH-secreting adenomas. The volume of residual tumor as a fraction of preoperative tumor volume was correlated with GH levels before and after surgery. Examination of this potential correlation required selection of patients with acromegaly who 1) had incomplete tumor removal, 2) had precise measurements of initial and residual tumor, and 3) were not on medical therapy. RESULTS Densely granulated tumors produced more peripheral GH per mass of tumor than sparsely granulated tumors (p = 0.04). There was a correlation between GH and IGF-1 levels (p = 0.001). Although there was no close correlation between tumor size and peripheral GH levels, after normalizing each tumor to its own plasma GH level and tumor volume, a comparison of percent tumor resection with percent drop in plasma GH yielded a high correlation coefficient (p = 0.006). CONCLUSIONS Densely granulated somatotropinomas produce more GH per mass of tumor than do sparsely granulated tumors. Each GH-secreting tumor has its own intrinsic level of GH production per mass of tumor, which is homogeneous over the tumor mass, and which varies greatly between tumors. In most patients the fraction of a GH-secreting tumor removed by surgery can be accurately estimated by simply comparing plasma GH levels after surgery to those before surgery.

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“…The latter can be easily recognised by the presence of juxtanuclear aggregates of intermediate filaments, namely fibrous bodies, showing a distinct immunohistochemical staining pattern using antibodies against cytokeratins (7,8). Recent findings suggest that these phenotypes could be associated with specific molecular characteristics as patients harbouring densely granulated somatotroph adenomas appear to respond better to medical treatment with somatostatin analogues (SSA) than those with the sparsely granulated tumours (9,10,11,12,13).…”

Section: Introductionmentioning

confidence: 99%

Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

Mayr

Buslei

Theodoropoulou

et al. 2013

European Journal of Endocrinology

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Objective: GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level. Methods: In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.Results: The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%). Conclusions: Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.

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Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly

Abstract: Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E-cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.

Cited by 181 publications

References 33 publications

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas

Percent reduction of growth hormone levels correlates closely with percent resected tumor volume in acromegaly

Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

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