Growth hormone tumor histological subtypes predict response to surgical and medical therapy

Abstract

Purpose Growth hormone (GH) pituitary tumors are associated with significant morbidity and mortality. Current treatments, including surgery and medical therapy with somatostatin analogues (SSA), dopamine agonists and/or a GH receptor antagonist, result in disease remission in approximately half of patients. Predictors of GH tumor response to different therapies have been incompletely defined based on histologic subtype, particularly densely (DG) versus sparsely (SG) granulated adenomas. The aim of this study was to examine our own institutional experience with GH adenomas and correlate how subtype related to clinical parameters as well as response to surgery and medical therapies. Methods A retrospective chart review of 101 acromegalic patients operated by a single neurosurgeon was performed. Clinical data were correlated with histologic subtype and disease control, as defined by IGF-1 levels, and random growth hormone levels in response to surgery and/or medical therapies. Results SG tumors, compared to DG, occurred in younger patients (p=0.0010), were 3-fold larger (p=0.0030), but showed no differences in tumor-invasion characteristics (p=0.12). DG tumors had a higher rate of remission in response to surgery compared to SG, 65.7% vs. 14.3% (p<0.0001), as well as to medical therapy with SSAs (68.8% for DG vs. 28.6% for SG tumors; p=0.028). SG tumors not controlled with SSAs consistently responded to a switch to, or addition of, a GH receptor antagonist. Conclusions Histological GH tumor subtyping implicates a different clinical phenotype and biologic behavior, and provides prognostic significance for surgical success and response to medical therapies.

Differential somatostatin receptor (SSTR) 1–5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors

“…Tumor tissues were submitted and fixed overnight in 10% buffered formalin as previously described (Kiseljak-Vassiliades et al, 2014). Briefly, sections from the paraffin blocks were cut at 4 microns and stained with hematoxylin and eosin, Gomori reticulin, and periodic acid Schiff-orange G histochemical stains.…”

“…Designation of subtypes of GH tumors based on specific histological markers including cytokeratin staining pattern, has also been associated with differential response to surgery (Bakhtiar, Hirano, Arita et al, 2010,Mazal, Czech, Sedivy et al, 2001,Kiseljak-Vassiliades, Carlson, Borges et al, 2014), as well as to SSAs as medical therapy (Bhayana, Booth, Asa et al, 2005,Ezzat, Kontogeorgos, Redelmeier et al, 1995,Fougner, Casar-Borota, Heck et al, 2012,Brzana, Yedinak, Gultekin et al, 2013,Bando, Sano, Ohshima et al, 1992). Densely granulated (DG) tumors, defined by perinuclear cytokeratin distribution, have shown a better response rate to medical therapy with SSAs compared to sparsely granulated (SG) tumors, characterized by dot-like keratin immunoreactivity commonly referred to as fibrous bodies (Bhayana et al, 2005,Ezzat et al, 1995,Fougner et al, 2012,Brzana et al, 2013,Bando et al, 1992).…”

A Consensus Statement on acromegaly therapeutic outcomes

“…Tumours showing dense GH granulation on pathology demonstrate greater responsiveness to first-generation SRL therapy than sparsely granulated adenomas 45,124,125 (LQ), whereas T2-hyperintense tumours are less likely to respond to SRL therapy than other tumours 48,126 (LQ). Other pathological markers, including immunohistochemistry to assess somatostatin receptor type 2 (SST2) and SST5 expression as well as dopamine receptor status 124,127 , might be useful for individualizing treatment decisions (VLQ).…”

Biomarkers of acromegaly

“…The papers of Kiseljak-Vassiliades et al [1] and Selek et al [2] published in this issue are significant because they focus on an important and unresolved problem of pituitary tumor prognosis, progression, and treatment. Many years ago, pituitary tumors were classified based only on their tinctorial properties using the hematoxylin-eosin stain and were classified as acidophilic, chromophobe, or basophilic adenomas.…”

“…Kiseljak-Vassiliades et al [1] reviewed the medical charts of 111 pituitary tumor patients diagnosed with acromegaly. The patients were operated by one neurosurgeon.…”