Thymic Hyperplasia after Treatment of ACTH-Dependent Cushing’s Syndrome Can Be Mistaken for a Thymic Epithelial Tumor

A 44-year-old woman presented to her local physician with headaches, weight gain, cystic acne, hypertension, depression, and fatigue. Physical examination revealed skin hyperpigmentation and a dorsocervical fat pad. Her urinary free cortisol levels were 69 μg/24 h and 42 μg/24 h (reference range 5.7–32). High-dose dexamethasone suppressed her serum cortisol level to 3.6 mmol/L. A pituitary magnetic resonance imaging scan showed a 5-mm tumor, and a diagnosis of Cushing's disease was made. Transphenoidal resection was performed and resulted in improvement of her symptoms. After surgery, the patient presented with hypercalcemia, and primary hyperparathyroidism was diagnosed. Multiple endocrine neoplasia type 1 was suspected, and a indium 111–labeled (111In) pentetreotide scan (OctreoScan [Mallinckrodt, Dublin, Ireland]) showed uptake in the anterior mediastinum, which was suggestive of a thymic neuroendocrine carcinoma (TNEC) (Fig. 1A–C). Computed tomography (CT) of the chest showed mediastinal enlargement but no obvious mass (Fig. 1D). Her 5-hydroxyindoleacetic acid and chromogranin A levels were normal. Because of worsening dry cough and a positive 111In-pentetreotide scan result, the patient underwent thymectomy by video-assisted thoracoscopic surgery. Pathological examination revealed benign thymic tissue with mild follicular hyperplasia and absence of adrenocorticotropic hormone expression (Fig. 2A and C). Two months later, bilateral neck exploration was performed with right inferior parathyroidectomy, and a nodular mass in the superior mediastinum was resected. Pathological examination of the mediastinal mass (Fig. 2B and D) and 10 resected lymph nodes showed no evidence of a TNEC. Four months after thymectomy, 111In-pentetreotide and CT scans of the chest showed postoperative changes and no evidence for a thymic epithelial tumor (TET) (Fig. 3A–D). One year after her last operation, CT scans of her chest remain unremarkable.Figure 2Microscopic findings of the mediastinal mass sampled at two independent times. (A and B) Images of sections from procedures 1 and 2, respectively. Typical hematoxylin and eosin staining shows normal appearing thymus, mainly composed of lymphocytes (thymocytes) and epithelial cells with a Hasall’s corpuscle (original magnification ×400). (C and D) Results of adrenocorticotropic hormone immunohistochemical staining on sections (A) and (B), respectively are negative.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Four months after thymectomy: Indium 111–labeled pentetreotide and computed tomography (CT) scans of the chest with negative results. Single-photon emission computed tomogragphy (SPECT) maximum intensity projection (A), axial SPECT at the level of the superior mediastinum (B), SPECT/CT scan fusion (SPECT in orange) (C), and CT (D). Surgical staples now seen in the superior mediastinum on CT.View Large Image Figure ViewerDownload Hi-res image Download (PPT) TETs are the most common cause of an anterior mediastinal mass in adults.1Carter B.W. Marom E.M. Detterbeck F.C. Approaching the patient with an anterior mediastinal mass: a guide for clinicians.J Thorac Oncol. 2014; 9: S102-S109Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar A subset of TNECs can cause Cushing’s syndrome, and these patients can present with an anterior mediastinal mass. Treatment of Cushing’s syndrome due to other causes can result in thymic hyperplasia (TH), which can also present as an anterior mediastinal mass and be mistaken for a TET. TH has also been described after chemotherapy and in patients with Grave’s disease.2Sun D.P. Ding C.Y. Wang L. et al.Thymic hyperplasia following chemotherapy in adults with lymphoma: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography findings and correlation with T cell repopulation.Leuk Lymphoma. 2015; 56: 2344-2349Crossref PubMed Scopus (5) Google Scholar, 3Dalla Costa M. Mangano F.A. Betterle C. Thymic hyperplasia in patients with Graves' disease.J Endocrinol Invest. 2014; 37: 1175-1179Crossref PubMed Scopus (21) Google Scholar Because TH can be misinterpreted as a TET, it is important to distinguish between these conditions owing to differences in management. TH after treatment of Cushing’s syndrome occurs as a result of activation of the immune system and “rebound” enlargement of the thymus upon resolution of hypercortisolism. Radiographic changes can be observed from 4 to 6 weeks to several months after normalization of cortisol levels. The natural history of TH in these cases is poorly understood. However, thymic enlargement resolves spontaneously and is associated with a benign clinical course (Table 1). Of note, normal thymic medulla contains high densities of somatostatin receptors, which can result in uptake on 111In-pentetreotide scan in patients with TH.8Reubi J.C. Waser B. Horisberger U. et al.In vitro autoradiographic and in vivo scintigraphic localization of somatostatin receptors in human lymphatic tissue.Blood. 1993; 82: 2143-2151PubMed Google Scholar In some cases, CT findings are helpful in distinguishing between TH and a TET.9Ackman J.B. Verzosa S. Kovach A.E. et al.High rate of unnecessary thymectomy and its cause. Can computed tomography distinguish thymoma, lymphoma, thymic hyperplasia, and thymic cysts?.Eur J Radiol. 2015; 84: 524-533Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Clinicians should be familiar with the pathophysiological and radiological changes associated with TH in patients successfully treated for Cushing’s syndrome to prevent misdiagnosing these cases as TETs and avoid thymectomy, which is generally not indicated under such circumstances.5Neto M.B. Machado M.C. Mesquita F. et al.Thymus hyperplasia after resolution of hypercortisolism in ACTH-dependent Cushing's syndrome: the importance of thymic vein catheterization.Eur J Endocrinol. 2006; 154: 807-811Crossref PubMed Scopus (8) Google Scholar, 6Schmidt S. Klose K.J. Frank M. Iwinska-Zelder J. Ehlenz K. Kisker O. [Reactive thymus dysplasia following therapy for ACTH-producing tumors].Radiologe. 1997; 37 ([in German]): 913-917Crossref PubMed Scopus (3) Google ScholarTable 1Systematic Review of the Literature on Patients Who Presented with Thymic Hyperplasia after Resolution of HypercortisolismReferencePatientsImaging FindingsTime of Presentation after Surgery or Medical ManagementSurgery (Thymectomy)HistopathologicDoppman et al.4Doppman J.L. Oldfield E.H. Chrousos G.P. et al.Rebound thymic hyperplasia after treatment of Cushing's syndrome.AJR Am J Roentgenol. 1986; 147: 1145-1147Crossref PubMed Scopus (30) Google ScholarACTH-dependent (ectopic source)CT chest on the 3 patients with reported widening mediastinum6 moNo—ACTH-dependent (ectopic source)3 moACTH-dependent (pituitary source)3 moNeto et al.5Neto M.B. Machado M.C. Mesquita F. et al.Thymus hyperplasia after resolution of hypercortisolism in ACTH-dependent Cushing's syndrome: the importance of thymic vein catheterization.Eur J Endocrinol. 2006; 154: 807-811Crossref PubMed Scopus (8) Google ScholarACTH-dependent (pituitary source)CT chest demonstrated enlargement of the thymus8 moNo—Schmidt et al.6Schmidt S. Klose K.J. Frank M. Iwinska-Zelder J. Ehlenz K. Kisker O. [Reactive thymus dysplasia following therapy for ACTH-producing tumors].Radiologe. 1997; 37 ([in German]): 913-917Crossref PubMed Scopus (3) Google ScholarACTH-dependent (pituitary source)CT chest in both patients reported enlargement of anterior mediastinum6 moNoThymic hyperplasia with negative immunostaining for ACTHACTH-independent (adrenal source)6 moYesTabarin et al.7Tabarin A. Catargi B. Chanson P. et al.Pseudo-tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases.Clin Endocrinol. 1995; 42: 207-213Crossref PubMed Scopus (21) Google ScholarACTH-dependent (ectopic source)CT chest triangular mediastinal mass8 moYesThymic hyperplasia with negative immunostaining for ACTHACTH-dependent (ectopic source)CT chest poorly defined mass in the anterior mediastinum6 moYesACTH-dependent (ectopic source)CT chest heterogeneous triangular mass11 moYesACTH-dependent (ectopic source)CT chest triangular mediastinal mass8 moYesACTH-dependent (ectopic source)CT chest thymic enlargement20 moNoACTH, adrenocorticotropic hormone; CT, computed tomography. Open table in a new tab ACTH, adrenocorticotropic hormone; CT, computed tomography. This research was supported in part by the Intramural Research Program of the Center for Cancer Research of the National Cancer Institute, National Institutes of Health.