Endocrine Abstracts

Recently, we provided the first integrated genomic classification of pituitary neuroendocrine tumors (PitNETs), on a series of 134 tumors. This series covered all histological, secretion, invasion and growth speed types. This molecular classification supports the importance of pituitary lineage as proposed by the World Health Organization 2017 classification, but also individualizes new entities. Indeed, corticotroph tumors are split into three distinct molecular groups. In addition sparsely granulated somatotroph tumors cluster with thyrotroph and pluri-hormonal-PIT1 tumors. Finally, “null-cell” are gonadotroph tumors.

Aim: To explore the clinical implications of this new molecular classification;

Method: For the series of 134 tumors with genomic characterization (transcriptome, exome, miRnome, methylome, SNParray), extensive data were collected, including clinical (size, sphenoid and cavernous invasion), hormonal, pathological (WHO2017) and outcome (aggressiveness) features.

Results: Immunohistochemistry thresholds:

Based on molecular classification, immunopositivity thresholds could be determined for prolactin, GH and ACTH in lacto-, somato- and corticotrophs.

-Aggressiveness:

On the whole cohort, aggressiveness did not appear as a major driver of genomic classification. The number of chromosomal alterations was not related to aggressiveness either, but rather to secretion type. Subgroup analyses revealed, for corticotrophs, an association between USP8 mutation status and aggressiveness. Indeed, USP8-mutated corticotrophs seemed less aggressive.

-Response to Temozolomide:

Temozolomide is currently recommended for treating aggressive tumors not responding to other treatments. Temozolomide is degraded by MGMT. The association between MGMT expression and response to temozolomide was evaluated in three patients. Expression level was high in one not responding, intermediate in one with partial response, and low in one with complete response. No negative correlation was found between MGMT expression and DNA methylation in MGMT locus on the whole cohort, including its promoter (median correlation coefficient 0.55; range: −0.27 to 0.76).

- Expression of somatostatin receptors:

Somatostatin receptor subtypes showed variable expression between molecular groups (Kruskal-Wallis test, P < 10–13 and P < 10–15 for SSTR2 and SSTR5, respectively). Notably, for corticotroph PitNETs, expression of SSTR5 was higher in USP8-mutated PitNETs compared with USP8-wild-type (Wilcoxon’s P < 10–4), supporting a potential value of USP8 mutation status for predicting response to pasireotide. Finally SSTR5 expression was also high in the group of thyrotroph tumors.

Conclusion: USP8-wildtype corticotroph adenomas with overt Cushing are more aggressive. MGMT promoter methylation is not correlated to MGMT expression. MGMT expression level may be associated to Temozolomide response. mRNA expression level could be a predictor of temozolomide. SSTR5 expression is high in USP8-mutated corticotroph tumors.