Clinicopathological Features of Growth Hormone-producing Pituitary Adenomas: Difference among Various Types Defined by Cytokeratin Distribution Pattern Including a Transitional Form

Abstract

Pituitary adenomas producing almost exclusively growth hormones (GH) have been ultrastructurally classified into two distinct types: densely granulated somatotroph (DG) adenomas and sparsely granulated (SG) adenomas. Fibrous body (FB), an intracytoplasmic globular aggregation of cytokeratin (CK) filaments, is a hallmark of SG adenomas. Under light microscope, FB could be identified by CK immunohistochemistry as a dot-pattern immunoreaction versus a perinuclear pattern for cells without FB. However, it has been noted that numerous adenomas contain mixed populations of the two patterns. To clarify clinicopathological characteristics of the adenomas with mixed populations ("intermediate type" adenomas) and to confirm clinicopathological differences between strictly defined DG-type and SG-type adenomas, we performed this study on 104 GH cell adenomas. Having segregated "intermediate-type" adenomas (26 cases), we found significant differences between typical DG-type (47 cases) and SG-type adenomas (31 cases); SG-type adenomas had younger ages (44 vs. 50), higher frequency of macroadenomas (86% vs. 58%), invasiveness (65% vs. 38%), advanced grades (3 or 4) in Knosp's classification (50% vs. 24%), and weaker immunoreaction for GH, beta-TSH, alpha-subunit, E-cadherin, and beta-catenin. Clinicopathological characteristics of "intermediate-type" adenomas were identical to those of DG-type adenomas. These findings confirm that SG-type adenoma is a distinct section of GH cell adenomas with special properties and biological behavior, and suggest that intermediate-phenotype adenomas are enrolled in DG-type adenomas. Special properties and biological behavior of SG-type adenomas may appear after the majority of tumor cells possess a fully developed fibrous body.

Relationship between cytokeratin staining patterns and clinico-pathological features in somatotropinomae

“…This finding coincides with the report of Mazal et al (11) and Obari et al (9). With respect to the tumour size, our findings were similar to the findings reported by Mazal et al (11) who also observed that DP adenomae were significantly larger than non-DP adenomae.…”

“…Other factors influencing tumour growth, such as apoptotic process, cell-cell junction and intercellular communication, should be further investigated to understand the linking mechanisms between CK expression and tumour growth. DP adenomae did not have the tendency to be more invasive than the other types; a finding that is inconsistent with the reports by Mazal et al (11) and Obari et al (9), where both groups determined invasion by Knosp grading (26). However, we evaluated the invasion into cavernous sinus based on intraoperative findings under microscopic and/or endoscopic observations in addition to preoperative MRI findings.…”

“…The perinuclear pattern (PP) and dot pattern (DP) in cytokeratin (CK) immunostaining observed under light microscopy can be good surrogate for the electron microscopic features of the DG and SG subtype adenomae respectively (1,6). However, there are some adenomae that exhibit a combined feature of PP and DP or the mixed pattern (MP) (7)(8)(9)(10)(11).…”

Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas

“…[3][4] As a consequence, differentiated adenomas usually exhibit diffuse adenohypophysial hormone positivity, with the exception of sparsely granulated somatotroph adenomas where positivity for GH can be focal and weak, however, the presence of fibrous bodies in 475% of tumor cells is identified. [3][4][5]22 In contrast to differentiated Pit-1 cell lineage adenomas, silent subtype 3 adenomas show variable, focal or scattered positivity for one or more adenohypophysial hormones including GH, PRL and beta-TSH. These features are consistent with a monomorphous plurihormonal adenoma of Pit-1 lineage in the vast majority of our cases.…”

AIP and the somatostatin system in pituitary tumours

“…Cytokeratin staining is used in clinical practice to characterise densely granulated adenomas having cytokertain staining with perinuclear pattern and sprasely granulated adenomas having dot-like pattern (Obari et al 2008). Sparsely granulated somatotrophinomas occur in younger patients, are larger and more invasive than densely granulated tumours and typically express SSTR5 but not SSTR2 (Mayr et al 2013), while densely granulated adenomas present higher levels of SSTR2 and are more responsive to SSA treatment (Obari et al 2008, Fougner et al 2012, Kato et al 2012, Brzana et al 2013, Larkin et al 2013.…”