Case Report: Progression of a Silent Corticotroph Tumor to an Aggressive Secreting Corticotroph Tumor, Treated by Temozolomide. Changes in the Clinic, the Pathology, and the β-Catenin and α-SMA Expression

Abstract

Clinically silent corticotroph tumors are usually macroadenomas that comprise 20% of ACTH tumors. They frequently progress to aggressive tumors with high recurrence, invasiveness, and on rare occasions, they may become hormonally active causing Cushing's disease. Trustable biomarkers that can predict their aggressive course, as well as their response to traditional or new therapies, are paramount. Aberrant β-Catenin expression and localization have been proposed as responsible for several malignancies including pituitary tumors. Nevertheless, the role of β-Catenin in the aggressive transformation of silent corticotropinomas and their response to Temozolomide salvage treatment have not been explored yet. In this work, we present a case of a silent corticotroph tumor that invaded cavernous sinus and compressed optic chiasm and, after a first total resection and tumor remission it recurred six years later as an aggressive ACTH-secreting tumor. This lesion grew with carotid compromise and caused Cushing's signs. It required multiple medical treatments including Cabergoline, Ketoconazole, TMZ, and radiotherapy. Besides, other two surgeries were needed until it could be controlled. Interestingly, we found α-SMA vascular area reduction and differential β-Catenin cell localization in the more aggressive tumor stages characterized by high Ki-67 indexes and p53 expression. Our results may indicate a role of angiogenesis and β-Catenin trigged events in the pituitary tumor progression, which could in turn affect the response to TMZ and/or conventional treatments. These molecular findings in this unusual case could be useful for future management of aggressive pituitary tumors.

Keywords: ACTH; corticotroph tumor; temozolomide; tumor transformation; vasculature; β-Catenin.

Figure 1

Timeline of disease progression and treatment. The scheme represents the course of the disease along time, including the diagnosis, hormone levels, and treatments. TSS, Transsphenoidal surgery; T4, thyroxine.

Figure 2

MRI images. (A) 2008-Preoperative pituitary MRI with gadolinium (sagittal view), evidencing a large pituitary mass with suprasellar extension and compression of the optic chiasm. (B) Postoperative MRI with gadolinium (sagittal view) showing complete tumor resection and decompression of the optic chiasm. (C) 2014-pituitary MRI (sagittal view) evidencing a tumor mass with extensive sphenoid and nasal invasion. (D) Postoperative MRI with gadolinium (sagittal image) showing partial resection with a remnant tumor in the nasal, sphenoid, and sellar region. (E) Control MRI in 2015 shows tumor regrowth in the sagittal image. (F) Postoperative MRI (sagittal view) showing less remnant tumor mass than in 2015. Tumor remains stable after radiotherapy and both cabergoline and ketoconazole treatment until 2021.

Figure 3

Pathology of the different tumor samples. The excised tumor tissue from the 2015 surgery showed high ACTH IR cells (A), increased Ki-67 proliferation index (B) and p53 immunoexpression (C) as we determined by IHC (20X, 40X, and 40X magnification, respectively). (D) Representative images of immunohistochemistry (IHC) for α-SMA of each tumor specimen obtained in 2008, 2014, and 2015 surgeries, respectively (10X magnification, scale: 50 µm). The vascular area (blood vessels area/total area), blood vessel size (µm2), and microvascular density (number of blood vessels/µm2) determined by α-SMA stained vessels are summarized in the table (E). Values correspond to the mean and standard error of two different experiments of immunohistochemistry. (F) Representative images of β-CATENIN immunoexpression in tumor samples of 2008, 2014, and 2015 surgeries, respectively (40X, scale: 30µm). (G) β-CATENIN positive cells at membrane, cytoplasm, and nucleus of tumor samples from 2014 and 2015 were counted and expressed as percentages of total nuclei (mean and SE).