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Silent or Subclinical Corticotroph Pituitary Macroadenoma Transforming Into Cushing Disease

2012; Lippincott Williams & Wilkins; Volume: 72; Issue: 1 Linguagem: Inglês

10.1227/neu.0b013e3182750850

1524-4040

Eugen Melcescu, Anthony W. Gannon, Andrew D. Parent, Jonathan Fratkin, William Nicholas, Christian A. Koch, Ayman Galhom,

Adrenal and Paraganglionic Tumors

To the Editor: Silent corticotroph adenomas (SCAs) are pituitary tumors with positive immunohistochemical staining for corticotropin (ACTH) but without clinical evidence of excess cortisol. Approximately 6% of all nonfunctioning pituitary adenomas are SCAs.1 The majority of SCAs are macroadenomas upon presentation and secrete mostly biologically inactive, high-molecular-weight ACTH. SCAs should be suspected in patients with high ACTH but normal cortisol levels (after excluding heterophil antibodies). In their large retrospective cohort of 33 patients with SCAs, Ioachimescu et al2 have recently challenged the notion that SCAs have high recurrence rates and aggressive behavior.3 Preoperatively, patients were not routinely screened for hypercortisolemia including measuring plasma ACTH, but 1 patient was found to have an elevated ACTH level and abnormal dexamethasone test results 6 months postoperatively.2 We retrospectively reviewed the University of Mississippi Medical Center pituitary database from 1979 to 2010 and identified 740 cases, 12 (1.6%) of which were histopathologically SCAs. One of these 12 patients had a 11-year follow-up, and this patient's SCA evolved into florid Cushing disease (CD). A 52-year-old black woman presented to an outside ear, nose, and throat clinic 11 years earlier because of nasal congestion and was found to have a posterior pharyngeal mass, which was biopsied. Pathology revealed a pituitary adenoma. An initial magnetic resonance imaging (MRI) (2000) demonstrated a normal-appearing pituitary gland, erosion of the sellar floor, and an exophytic pituitary mass growing into the sphenoid sinus. No clinical features of Cushing syndrome (CS) were present. Hormonal workup and weight over time are shown in Figure A and D: ACTH 168 pg/mL (normal, 10-60), serum cortisol 15.7 μg/dL (6 AM), s-cortisol 13.3 μg/dL (3 PM), 24-hour urinary free cortisol (UFC) 45.3 μg/24 h (2.0-42.4). The patient underwent transsphenoidal resection in 2000. Pathology revealed a pituitary adenoma staining positively for ACTH. Her last pituitary pathology (2010) showed pituitary adenoma "null-cell" type with a negative ACTH stain (Figure B). Follow-up imaging demonstrated the presence of a residual tumor. Two years later (2002), she had developed CS and uncontrolled diabetes mellitus. Repeat MRI demonstrated an enlarged pituitary adenoma. The 24-hour UFC value increased remarkably to 1861 μg/24 hours. She underwent repeat transsphenoidal resection in 2002 and postoperative radiotherapy (4500 rad) in 2004. In 2005 (Figure C), another MRI showed a 50% tumor size reduction (images 1 and 2); ACTH was 129 pg/mL. Ten years after the initial presentation (2010), she had pituitary mass recurrence and CN III palsy (images 3 and 4). She subsequently received a third transsphenoidal resection and now has an unresectable tumor (images 5 and 6). Hormonal workup: ACTH 171 pg/mL and s-cortisol 26 μg/dL. Her weight over time is shown in Figure D.FIGURE: A, main laboratory data and weight plot for our case. B, appearance of the resected adenoma over time: comparing hematoxylin and eosin with ACTH stain. C, 1+2, pituitary MRI in 2005; 3+4, preoperative MRI showing recurrence of the adenoma (April 1, 2010) - sella/suprasellar and parasellar mass that has increased in size, involving the skull base/clivus with mild suprasellar extension; 5+6, postsurgical MRI (April 28, 2010) - residual tumor involving the right cavernous sinus, middle cranial fossa, and Meckel cave. D, weight changes over time. H&E, hematoxylin and eosin; ACTH, corticotropin; FC, free cortisol; MRI, magnetic resonance imaging.Predicting the biological behavior of SCAs is challenging.2-4 Univariate and multivariate analyses about predictors of the recurrence of nonfunctioning pituitary adenomas (NFPAs) found that cavernous sinus invasion and the specific combination of subtotal resection/radiotherapy jointly predicted NFPA recurrence. Time to first recurrence was significantly shorter in SCAs in comparison with the time of recurrence of NFPAs. An SCA hazard ratio was 5.6.3,4 SCAs usually present as macroadenomas as opposed to CD (microadenomas).3 Resection of large tumors can thus be more challenging as shown in our case. The Cushing phenotype is usually not apparent in these patients because of abnormal ACTH structure, diminished adrenal gland responsiveness, or simply lower levels of ACTH expression. For unclear reasons, SCAs have a potential for evolving into CD, and it is not currently possible to predict in which patient this evolution will occur.5 Underlying yet undiscovered or unrecognized genetic predispositions are likely the cause and may be triggered by radiation. Markers such as p53, the Ki-67 and high mitosis index, all usually used to call adenomas atypical, are inconsistently expressed in SCAs.3 We recommend first excluding heterophil ACTH antibody in patients presenting with a pituitary adenoma, elevated plasma ACTH but normal serum and UFC levels, and no clinical features of CS.6 This can be done by using the gel chromatography technique for detecting high-molecular-weight ACTH in such patients. Analogous to patients with adrenal incidentalomas and no clinical features of CS, patients with pituitary tumors including SCAs may have to undergo a preoperative dexamethasone test and evaluation of subclinical hypercortisolemia. This case underscores that patients with SCAs will need long-term follow-up until better predictive biomarkers are identified. Disclosures The authors have received fellowship support from the Department of Medicine, University of Mississippi Medical Center. Prof Koch discloses that he has served as Principal Investigator of the SEISMIC study and the TR321 trial, and as a consultant for Novo Nordisk. He is presently a speaker for IPSEN. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.