ASIAN CARDIOVASCULAR & THORACIC ANNALS
Appearance of a thymic mass after treatment of Cushing’s syndrome
Alessandro P Delitala’, Laura Olita’, Carla Piras’, Rossella Cosseddu’, Giorgio Bagella2 and Giuseppe Fanciulli1,3
Asian Cardiovascular & Thoracic Annals 2017, Vol. 25(2) 150-153 @ The Author(s) 2016 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492316686480 journals.sagepub.com/home/aan SSAGE
Abstract
A 23-year-old woman was referred to our center with hirsutism, acne, weight gain, weakness, and irregular menses. Laboratory tests revealed increased levels of cortisol and sex hormones, and reduced adrenocorticotropic hormone levels. The patient underwent a right adrenalectomy. Pathology of the resected right adrenal gland showed an adrenal carcinoma. Computed tomography 8 months after the surgery revealed a thymic mass that was not detected preopera- tively. The frequency of rebound thymic hyperplasia after normalization of hypercortisolism is not known, but possibly as high as 40%. Physicians must be aware of this phenomenon to avoid unnecessary thoracic surgery.
Keywords
Adrenocorticotropic hormone, Carcinoid tumor, Cushing syndrome, Hydrocortisone, Thymus neoplasms, Thymus hyperplasia
Introduction
The presence of a thymic mass in patient with active Cushing’s syndrome (CS) is a well-known potential cause of CS. Conversely, the appearance of a new thymic mass after normalization of hypercortisolism in patients with CS poses a crucial clinical dilemma for the endocrinologist. Should this mass be considered a potentially risky (neoplastic) condition? What is the correct approach (surgery or radiological follow-up)? No specific studies aimed to evaluate the frequency of the appearance of thymic masses after normalization of hypercortisolism nor guidelines or expert opinions con- cerning the management of this condition could be found in the medical literature.
Case report
A 23-year-old woman was referred to our center com- plaining of hirsutism, acne, weight gain, weakness, and irregular menses. Physical examination revealed truncal obesity, supraclavicular fat pads, and a buffalo hump. Laboratory tests showed increased blood cortisol (38.4 µg.dL-1; normal range 5-25; 1,059 µg.mL-1), estradiol (1,238 pg·mL-1; 4,545 pmol·L-1), dehydroe- piandrosterone sulfate (>10,000 ng.mL -; normal
range 1,200-3,600 ng·mL-1; > 3,180 nmol·L-1), total tes- tosterone (666 µg.dL -; normal range 0-100 µg.dL-1; 18,374.94 nmol·L-1), free testosterone (49.08 pg.mL-1; normal range 0.5-3.18 pg.mL-1;170.2 pmol.L-1), and reduced adrenocorticotropic hormone (ACTH) levels (0.88 pg.mL-1; normal range 9-52pg.mL-1; 3.1 pmol·L-1). An overnight suppression test with dexa- methasone (1 mg orally at 11.00 pm) confirmed hypercor- tisolism (plasma cortisol at 8.00 pm the next day was 35.7 µg.mL-1; 1,035 umol.L-1). Computed tomography (CT) of the abdomen showed an 11-cm right adrenal mass. The patient underwent a right adrenalectomy, and the pathological report revealed an adrenocortical carcinoma (Figure 1). Postsurgery laboratory tests showed cortisol 0.6 µg-dL-1 (0.02 umol.L-1), estradiol
“Internal Medicine Unit, University Hospital of Sassari, Sassari, Italy 2Radiology Unit, University Hospital of Sassari, Sassari, Italy
3Department of Clinical and Experimental Medicine, University Hospital of Sassari, Sassari, Italy
Corresponding author:
Alessandro P Delitala, Internal Medicine Unit, Clinica Medica, Azienda Ospedaliero-Universitaria di Sassari, Viale San Pietro 8, 07100 Sassari, Italy.
Email: aledelitala@tiscali.it
18 pg.mL-1 (66 pmol·L-1), dehydroepiandrosterone sul- fate 77.7 ng.mL-1 (244.86 nmol.L-1), total testosterone 27.85 µg-dL-1 (768.38 nmol.L-1), and free testosterone 0.58 pg.mL-1 (2.0 pmol.L-1). The patient underwent adjuvant chemotherapy with mitotane, and adrenal replacement therapy with fludrocortisone and hydrocor- tisone. CT at 8 months postoperatively revealed a 6 × 4.5 × 2cm thymic mass (Figure 2a) that had not been present in the preoperative scan. Positron-emission tomography with 18F-flourodeoxyglucose showed no pathological uptake (maximum standardized uptake value 2.9) at the mediastinal level. The case was brought to the attention of the local tumor board, prompting a systematic literature search on this phenomenon; the results are summarized in Table 1.
Discussion
A thymic mass is a challenge for the physician because several conditions can cause thymus enlargement.
Thymic hyperplasia can be observed after termination of stressful conditions such as recovery after chemo- therapy, burns, and cardiovascular surgery.1 The mech- anism behind this phenomenon is thought to be depletion of lymphocytes within the thymus due to the high cortisol concentration, followed by rebound hyperplasia of the gland when the cortisol level falls.2 Enlargement of the thymus is often seen in patients with myasthenia gravis; the thymus usually appears as a sharply marginated area with smooth or lobulated borders on a CT scan. Symptoms of myasthenia gravis and clinical history help to identify the cause. Thymoma in these patients has an indolent course, although invasive high-stage malignant lesions have been described. The frequency of the appearance of a thymic mass after normalization of hypercortisolism in patients with CS is unknown. The only available data can be extrapolated from a study on 85 patients with CS performed in 1999;3 the authors stated that 40% of patients (4/10) who underwent thoracic examinations after normalization of hypercortisolism displayed thymic enlargement. The medical literature describes 16 patients with CS in whom the appearance of a thymic mass after normalization of hypercortisolism was observed:2-8 7/16 underwent thymic resection, and pathological examinations consistently showed thymic hyperplasia (increase in the size and weight of the thymus with preservation of its microscopic fea- tures); 6/16 had radiological follow-up with well- documented spontaneous regression of the mass in 2 patients (at 12 and 38 months), and no data were avail- able for the remaining 3/16 patients (Table 1).
Given the results of our literature search, we opted for radiological follow-up in our patient. The CT scan performed 3 years after surgery confirmed regression of the thymic mass (Figure 2b). Whereas the preexistence of a thymic lesion or thymic enlargement in patients with ACTH-dependent CS raises the possibility of
(a)
(b)
| Case no. | Age (years) | Sex | Underlying disease | Time to appearance of thymic mass after normalization of hypercortisolism | Radiological features* | Surgical treatment/ radiological follow-up | Author |
|---|---|---|---|---|---|---|---|
| 1 | 15 | M | ACTH-secreting pitu- itary microadenoma | 3 months | Anterior mediastinal mass (CT) | NR | Doppman4 (1986) |
| 2 | 27 | F | ACTH-secreting bron- chial carcinoid | 6 months | Anterior mediastinal mass (CT) | NR | Doppman4 (1986) |
| 3 | 35 | M | Ectopic ACTH pro- duction (occult) | 3 months | Triangular mass (CT) | NR | Doppman4 (1986) |
| 4 | 59 | F | ACTH-secreting bron- chial carcinoid | 8 months | 3-cm triangular mass (CT?) | Thymectomy | Tabarin8 (1995) |
| 5 | 44 | M | ACTH-secreting bron- chial carcinoid | 5 months | 3-5-cm mass (CT?) | Thymectomy | Tabarin8 (1995) |
| 6 | 30 | M | Ectopic ACTH pro- duction (occult) | 11 months | 3-cm triangular mass (CT?) | Thymectomy | Tabarin8 (1995) |
| 7 | 33 | F | ACTH-secreting bron- chial carcinoid | 8 months | 3-6-cm triangular mass (CT?) | Thymectomy | Tabarin8 (1995) |
| 8 | 37 | F | ACTH-secreting bron- chial neuroendo- crine carcinoma | 11 months | 5-cm quadrangular mass (MRI) | Radiological follow-up (spontaneous regression in 12 months) | Tabarin8 (1995) |
| 9 | 48 | F | ACTH-secreting pitu- itary microadenoma | 6 months | Mediastinal mass (CT) | Thymectomy | Schmidt6 (1997) |
| 10 | 33 | M | Ectopic ACTH pro- duction (occult) | 6 months | Enlargement (CT) | Thymectomy | Schmidt6 (1997) |
| 11 | 42 | F | NR | Median 16 months | 18 × 10-mm nodule (CT) | Radiological follow-up™ | Hanson3 (1999) |
| 12 | NR | NR | NR | Median 16 months | Enlargement (CT) | Radiological follow-up™ | Hanson3 (1999) |
| 13 | NR | NR | NR | Median 16 months | Enlargement (CT) | Radiological follow-up | Hanson3 (1999) |
| 14 | NR | NR | NR | Median 16 months | Enlargement (CT) | Radiological follow-up1 | Hanson3 (1999) |
| 15 | 48 | F | Ectopic ACTH pro- duction (occult) | 8 months | 3-cm nodule (CT) | Radiological follow-up (spontaneous regression in 38 months) | Neto5 (2006) |
| 16 | 27 | M | ACTH-secreting bron- chial carcinoid | 3 months | Triangular mass (CT) | Thymectomy | Icard2 (2013) |
*As reported in the article. “Radiological follow-up was reported up to 124 months for cases II to 14. ACTH: adrenocorticotropic hormone; CT: computed tomography; MRI: magnetic resonance imaging; NR: not reported.
development from this site (as described in 11.2% of cases), we suggest that the appearance of a thymic mass after resolution of hypercortisolism should be regarded as rebound thymic hyperplasia until otherwise proven. In doubtful cases, CT can greatly help the clinician because an ACTH-secreting thymic carcinoid is usually associated with a nodular contour, and frequently con- tains necrotic or calcified foci, whereas thymic rebound hyperplasia typically shows diffuse enlarge- ment, a fine mixture of fat and lymphoid tissue, a smooth contour, normal vessels, and it maintains a tri- angular shape. Although baseline measurement of the thymus did not add further information due to the vari- ations in benign and malignant neoplasms, differences in size and shape during follow-up might help to evalu- ate the lesion.
Acknowledgment
We wish to thank Dr. Luca Pes for his valuable help in editing the manuscript.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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