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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 602-605
Copyright © 1999 by The Endocrine Society

Original Studies

Computed Tomography Appearance of the Thymus and Anterior Mediastinum in Active Cushing’s Syndrome

J. A. Hanson, S. A. Sohaib1, J. Newell-Price, N. Islam, J. P. Monson, P. J. Trainer, A. Grossman, G. M. Besser and R. H. Reznek

Departments of Diagnostic Imaging (J.A.H., S.A.S., R.H.R.) and Endocrinology (J.N-P., N.I., J.P.M., P.J.T., A.G., G.M.B.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE

Address all correspondence and requests for reprints to: Dr. S. A. Sohaib, Department of Diagnostic Imaging, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom. E-mail: S.A.Sohaib{at}mds.qmw.ac.uk


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Computed tomography (CT) evaluation of the thymus and anterior mediastinum is an important aspect of the investigation of patients with ACTH-dependent Cushing’s syndrome in order to exclude an ACTH-secreting carcinoid tumor. We have reviewed the CT imaging of the thymus and anterior mediastinum in a series of 85 patients (55 females; median age 41, range 7–77 yr) with active Cushing’s syndrome as there are few data on the range of appearances in hypercortisolemic states. One patient had a thymic carcinoid tumor (24 x 18 mm). Of the others, 28/84 (33%) patients showed thymic remnant tissue, consisting of either nodule(s) at least 5 mm diameter (n = 21, mean diameters 12.5 ± 5 x 9.6 ± 4 mm), or triangular bilobed glands (n = 7, mean thickness of the body, right and left limbs 25 ± 7, 14 ± 3, and 12 ± 5 mm). Thymic involution appeared in 56/84 (67%) patients, ranging from small nodule(s) of less than 5mm diameter to linear soft tissue strands and complete fatty replacement. Patients with thymic remnant tissue were younger than those with thymic involution (P < 0.05). The thymic carcinoid tumor could be distinguished from remnant tissue on the basis of age and size. The presence of anterior mediastinal nodule(s) in hypercortisolemia need not imply the presence of a thymic carcinoid tumor, although in older patients this should arouse suspicion.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ACTH-DEPENDENT Cushing’s syndrome is caused by the secretion of ACTH from an ectopic nonpituitary source in 10–15% of patients. In as many as 50% of these cases, the site of ectopic ACTH hypersecretion is occult, with possible sources including a thymic carcinoid (1). The search for an ACTH-secreting source includes rigorous cross-sectional imaging and venous sampling studies (2). Exclusion of a thymic carcinoid tumor is thus an important objective, and at our institution, computed tomography (CT) of the anterior mediastinum forms part of the evaluation of a patient with ACTH-dependent Cushing’s syndrome.

However, there are few data on the range of CT appearances of the thymus in Cushing’s syndrome. Apoptosis of thymic cells follows exposure to excess glucocorticoids (3), and thymic involution, assessed by plain radiography, occurs in hypercortisolemic states (4). Despite these reports, we have observed persistence of substantial thymic remnant tissue in a number of patients undergoing investigation for active Cushing’s syndrome, causing a diagnostic dilemma. We have therefore reviewed the thoracic CT imaging in a series of patients with active Cushing’s syndrome in order to define the range of appearances of the anterior mediastinum in these patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We reviewed the case records and imaging of 85 patients (55 females; age median 41, range 7–77 yr) with biochemically active Cushing’s syndrome attending St Bartholomew’s Hospital between 1978 and 1996 who had undergone thoracic CT. The etiology of the Cushing’s syndrome is shown in Table 1Go. In 8 patients the source of ACTH secretion remained unknown despite a median follow-up of 9 (range 8–12) yr. All 8 received medical therapy to lower cortisol levels, with 3 undergoing negative trans-sphenoidal exploration and 4 requiring bilateral adrenalectomy. One of the 8 patients died within a year of investigation, but post-mortem evaluation failed to reveal the source of ACTHhypersecretion.


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  		Table 1. Etiology of Cushing’s syndrome

 
Active Cushing’s syndrome was diagnosed by established criteria, which included loss of circulating cortisol circadian rhythm, dexamethasone nonsuppressibility, and a mean serum cortisol level of more than 10.8 mcg/dL (300 nmol/L) [sampling times 0900, 1200, 1500, 1800, 2100 h (5)].

The CT scans of the anterior mediastinum were reviewed by one observer (R.H.R.) who was blinded to the patients’ age and endocrine status. Imaging was performed using the following CT systems: EMI 5005 (1978–1982), GE 9800 (1983–1992), and GE High Speed Advantage (1993–1996) (GE Medical Systems, Milwaukee, WI). Scans were obtained using contiguous 5 or 10 mm sections. The patients were divided into 5 groups according to the anterior mediastinal appearances: I), fat replacement with no soft tissue; II), linear strands of soft tissue; III), single or multiple small nodules less than 5mm diameter; IV), single or multiple larger nodule(s) of at least 5 mm diameter; V), triangular bilobed thymus gland (Fig. 1Go). The long (L) and short (S) axis diameters of larger nodules (group IV) were determined. The thickness of the body and limbs of triangular glands (group V) were measured, as defined in Fig. 2Go. These measurements were made using callipers on hard copy films.



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  		Figure 1. A-F, Axial CT scans of the anterior mediastinum showing range of thymic appearances. A, Fat replacement of the anterior mediastinum with no soft tissue (I) in a 73-yr-old women. B, Linear strands of soft tissue within the anterior mediastinum (II) in a 52-yr-old woman. C, Multiple small nodules < 5 mm diameter within anterior mediastinum (III) in a 31-yr-old man. D and E, Two examples of larger than 5 mm nodules within the anterior mediastinum (IV) in a 27-yr-old woman and 28-yr-old man respectively. F, Triangular bilobed thymus gland (V) in a 7-yr-old boy.

 


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  		Figure 2. Schematic representation of triangular bilobed thymus gland with measurements indicated. Distance (1 ) - thickness of body; distance (2 ) - thickness of left limb.

 
Statistical evaluation including analysis of variance (one-way ANOVA) was performed using the SPSS software package. Significance was taken as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The relationship between anterior mediastinal appearance, age, and mean serum cortisol is shown in Table 2Go. All patients (6/6, or 100%) younger than 20 yr of age, and 19/36 (53%) patients 20–39 yr of age, were found to have substantial soft tissue (groups IV and V) in the anterior mediastinum. Of patients 40 yr or more, 38/43 (88%) displayed features of involution (group I-III appearances), and in 15/43 (35%), there was complete fatty replacement. Between-groups comparison (one-way ANOVA) demonstrated that those patients with substantial soft tissue (groups IV and V) were significantly younger (P < 0.02) than those with a more involuted thymus (groups I-III). No relationship was identified between mean serum cortisol levels and anterior mediastinal appearance, using a between-groups comparison.


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  		Table 2. Relationship between anterior mediastinal appearance at CT, age and mean serum cortisol level

 
In this series, CT detected a 24 x 18 mm thymic carcinoid tumor in a 42-yr-old female patient with the ectopic ACTH syndrome. Two patients with the syndrome of ACTH secretion of unknown origin had anterior mediastinal nodules, which were presumed not to represent carcinoid tumors on the basis of 8 yr of radiological follow-up in one case, and post-mortem examination in the other.

Excluding the patient with the thymic carcinoid, the mean long (L) and short (S) axis diameters of the larger nodules present in 21 patients (group IV) were 12.5 ± 5 mm and 9.6 ± 4 mm. Nodule area ({pi} x L/2 x S/2) was plotted against age (Fig. 3Go). The thymic carcinoid tumor was substantially larger than remnant thymic nodules occurring in the remaining patients with Cushing’s syndrome of similar age. The mean thicknesses of the body, right and left limbs of the triangular bilobed glands (group V), were 25 ± 7.0 mm, 14 ± 3.0 mm, and 12 ± 5.0 mm respectively.



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  		Figure 3. Scatter plot showing relationship between 5 mm thymic nodule area (in group IV) and age (22 patients). •, Pituitary Cushing’s syndrome due to known ACTH source (n = 15). {blacktriangleup}, Ectopic ACTH secretion (n = 3). {diamondsuit}, ACTH secretion of unknown source (n = 2). {blacksquare}, Cushing’s syndrome due to adrenal tumor (n = 1). {circ}, Thymic carcinoid tumor (n = 1).

 
Ten patients underwent at least one follow-up thoracic CT examination during a period of up to 124 months with a normal mean serum cortisol. Four of these patients displayed degrees of rebound enlargement, occurring within 10–24 months (median 16 months). This was most marked in a 42-yr-old female, in whom an 18 x 10 mm nodule developed in a previously fat-replaced anterior mediastinum. Of the remaining patients, 4 demonstrated unchanged findings, while 2 showed thymic involution.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this series, 33% of patients with active Cushing’s syndrome had significant thymic soft tissue remnant structures in the anterior mediastinum on CT. The predominant influence on anterior mediastinal appearance was age, with greater degrees of involution found in older patients. Within each age group, however, considerable variation in thymic morphology was observed. No relationship with mean serum cortisol levels was identified. We did not attempt to correlate the duration of active Cushing’s syndrome to the presence of soft tissue in the anterior mediastinum because of the difficulty in totally accurately defining the onset of disease.

There may be overlap between the appearances of thymic remnant tissue and a small thymic carcinoid tumor, which is of critical importance in the investigation of patients with ACTH-dependent Cushing’s syndrome. The tumors reported ranged widely in size at presentation, from 3 to 20 cm diameter, and those associated with clinically apparent hormone hypersecretion tended to be smaller (6, 7, 8, 9, 10). CT is currently the optimal method for diagnosis (11).

Our institution is a tertiary referral center, and in our experience of over 350 cases of Cushing’s syndrome since 1969, we have diagnosed two patients with a carcinoid tumor of the thymus (8), one of whom is included in this series. The second patient (a 42-yr-old male) was found to have a 40 x 30 x 10 mm anterior mediastinal carcinoid tumor at surgery (1, 8). Although thymic carcinoid tumors are rare, the diagnostic dilemma occurs in a substantial number of patients being investigated. Our results show that in older patients age 40 yr or more, confusion between a thymic tumor and remnant tissue should not arise. There is less thymic remnant soft tissue, and a nodule in a patient over 40 yr of age warrants a high degree of suspicion that it represents the source of ACTH secretion.

To what extent do thymic appearances in active Cushing’s syndrome differ from the expected spectrum of involution seen in normal individuals? There are published studies on the range of CT appearances of the thymus, stratified according to age, but these have limitations (12, 13). A lot of the data are descriptive, with quantitative measurements possible in only 30% of patients in one series (13). Indications for scanning included extrathoracic malignancy, sepsis, and trauma (13). It is recognized that malignant disease is associated with adrenal hyperplasia and altered cortisol dynamics (14), and these factors may also influence thymic morphology. Accepted findings for normal thymic appearance are progressive reduction in limb thickness as age increases above 20 yr, typically on the order of 10 mm decreasing to 5 mm (13), complete fatty replacement by 40 yr of age in about 50% of patients, and no thymic remnant tissue seen to exceed 7 mm in short axis diameter in patients more than 40 yr of age (13). We found that all patients less than 20 yr of age and 53% age 20–39 yr had substantial anterior mediastinal soft tissue. In contrast, only 5/35 (14%) patients more than 40 yr of age showed thymic remnant soft tissue. In active Cushing’s syndrome, therefore, changes in thymic appearance are influenced by age and mirror the progressive involution previously described in the general population of patients undergoing CT. Hypercortisolemia, to the degree typically found in Cushing’s syndrome, does not cause complete thymic involution in all patients.

Glucocorticoids cause apoptosis of mouse thymic cells in vitro (3). Furthermore, thymic atrophy and rebound hyperplasia have been described to occur radiologically in response to an elevation and reduction, respectively, of serum cortisol levels (4, 15, 16, 17). In light of these observations, it is difficult to explain the persistence of substantial thymic tissue in a moderate number of patients with active Cushing’s syndrome. It may be that thymic stroma and epithelial tissues have more varied resistance to the effects of hypercortisolemia than the lymphocyte component.

Our aim in this study was not to make a formal comparison between thymic appearances in Cushing’s syndrome and nonhypercortisolemic patients, but to clarify the extent of the problem of differential diagnosis. We suggest that the detection at CT of an anterior mediastinal soft tissue nodule in a patient with active Cushing’s syndrome need not be problematic, but could be further investigated as follows: in patients over 40 yr of age, the presence of a soft tissue nodule larger than 15 x 15 mm should arouse strong suspicion of a thymic carcinoid. In contrast, such structures are expected in patients less than 20 yr of age. In the intermediate 20–39-yr age group, remnant thymic tissue will be observed approximately half the time. Should a complete series of investigations fail to reveal the source of ectopic ACTH secretion, diagnostic difficulty may then arise. Follow-up CT could provide reassurance that the nodule size is stable or regressing. Increasing size after normalization of cortisol levels is likely to reflect rebound hyperplasia. Mediastinal vein sampling studies may be of value in this situation. Indeed, elevated ACTH levels were present in the mediastinal veins of the patient with a thymic carcinoid tumour (1). It should be noted, however, that this is complex to perform and should only be done in experienced centers; even then the results are not always readily interpretable (2, 18).

We have confirmed that the demonstration, on CT, of substantial anterior mediastinal soft tissue in a patient over 40 yr of age undergoing investigation for ACTH-dependent Cushing’s syndrome should warrant suspicion that this represents an ACTH-secreting thymic carcinoid tumor. In younger patients it must be recognized that the presence of nodules 10–15 mm in diameter is common.


   Footnotes
 
1 Dr. S. A. A. Sohaib was supported in part by the Joint Research Board, St. Bartholomew’s Hospital, London, United Kingdom. Back

Received July 2, 1998.

Revised October 21, 1998.

Accepted November 11, 1998.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Vincent JM, Trainer PJ, Reznek RH, et al. 1993 The radiological investigation of occult ectopic ACTH-dependent Cushing’s syndrome. Clin Radiol. 48:11–17.[CrossRef][Medline]
  2. Newell-Price JDC, Trainer PJ, Besser GM, Grossman AB. 1998 The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev. In press.
  3. Cohen JJ. 1992 Glucocorticoid-induced apoptosis in the thymus. Semin Immunol. 4:363–369.[Medline]
  4. Caffey J, Dilberti C. 1959 Acute atrophy of the thymus induced by adrenocorticoids observed roentgenographically in living human infants. AJR. 82:530–540.
  5. Trainer PJ, Eastment C, Grossman AB, Wheeler MJ, Perry L, Besser GM. 1993 The relationship between cortisol production rate and serial serum cortisol estimation in patients on medical therapy for Cushing’s syndrome. Clin Endocrinol (Oxf). 39:441–443.[Medline]
  6. Rosai J, Higa E. 1972 Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumour. Cancer. 29:1061–1074.[CrossRef][Medline]
  7. Wick MR, Scott RE, Li C-Y, Carney JA. 1980 Carcinoid tumour of the thymus: a clinicopathologic report of seven cases with a review of the literature. Mayo Clin Proc. 55:246–254.[Medline]
  8. Howlett TA, Drury PL, Perry L, Doniach I, Rees LH, Besser GM. 1986 Diagnosis and management of ACTH-dependent Cushing’s syndrome: comparison of the features in ectopic and pituitary ACTH production. Clin Endocrinol (Oxf). 24:699–713.[Medline]
  9. Wollensak G, Herbst EW, Beck A, Schaefer H-B. 1992 Primary thymic carcinoid with Cushing’s syndrome. Vichows Arch A Pathol Anat. 420:191–195.
  10. Wang D-Y, Chang D-B, Kuo S-H, et al. 1994 Carcinoid tumours of the thymus. Thorax. 49:357–360.[Abstract/Free Full Text]
  11. Brown LR, Aughenbaugh GL, Wick MR, Baker BA, Salassa RM. 1982 Roentgenologic diagnosis of primary corticotropin-producing carcinoid tumours of the mediastinum. Radiology. 142:143–148.[Abstract/Free Full Text]
  12. Baron RL, Lee JKT, Sagel SS, Petersen RR. 1982 Computed tomography of the normal thymus. Radiology. 142:121–125.[Abstract/Free Full Text]
  13. Francis IR, Glazer GM, Bookstein FL, Gross BH. 1985 The thymus: reexamination of age-related changes in size and shape. AJR. 145:249–254.[Abstract/Free Full Text]
  14. Vincent JM, Morrison ID, Armstrong P, Reznek RH. 1994 Computed tomography of diffuse, non-metastatic enlargement of the adrenal glands in patients with malignant disease. Clin Radiol. 49:456–460.[CrossRef][Medline]
  15. Doppman JL, Oldfield EH, Chrousos GP, et al. 1986 Rebound thymic hyperplasia after treatment of Cushing’s syndrome. AJR. 147:1145–1147.[Abstract/Free Full Text]
  16. Tabarin A, Catargi B, Chanson P, et al. 1995 Pseudo-tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases. Clin Endocrinol (Oxf). 42:207–213.[Medline]
  17. Gelfand DW, Goldman AS, Law AJ. 1972 Thymic hyperplasia in children recovering from thermal burns. J Trauma. 12:813–817.[Medline]
  18. Doppman JL, Pass HI, Nieman LK, et al. 1992 Corticotropin-secreting tumors of the thymus: diagnostic unreliability of thymic venous sampling. Radiology. 184:71–74.[Abstract/Free Full Text]



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