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Ann Thorac Surg 2002;73:675-681
© 2002 The Society of Thoracic Surgeons

Review

Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome

Marc de Perrot, MDa, Anastase Spiliopoulos, MDb, Stefan Fischer, MDa, Martin Totsch, MDc, Shaf Keshavjee, MD*a

a Division of Thoracic Surgery, Toronto General Hospital, Toronto, Canada
b Clinic of Thoracic Surgery, University Hospital of Geneva, Geneva, Switzerland
c Division of Clinical Pathology, University Hospital of Geneva, Geneva, Switzerland

* Address reprint requests to Dr Keshavjee, Division of Thoracic Surgery, Toronto General Hospital, 200 Elizabeth St, EN 10-224, Toronto, M5G 2C4 Ontario, Canada
e-mail: shaf.keshavjee{at}uhn.on.ca


   Abstract
Top
 Abstract
Introduction
 Case reports
 Comment
 References
 
Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome is a rare disease. Recent evidence suggests that these tumors form part of a continuous spectrum ranging from well-differentiated carcinomas to small cell carcinomas. We report two new cases and review the 23 cases reported in the literature since 1972. The different diagnostic modalities are discussed, and an algorithm for the diagnosis of ectopic secretion of adrenocorticotropin (ACTH) is presented. In the future, the advent of radiologic and nuclear imaging as well as more accurate workup should help to diagnose these tumors at an earlier stage and improve the long-term outcome.


   Introduction
Top
 Abstract
 Introduction
Case reports
 Comment
 References
 
Since the first description of thymic carcinoid as a specific entity in 1972 by Rosai and Higa [1], approximately 150 cases have been reported in the literature [1–3]. These tumors are frequently associated with endocrinopathies and carry a poor prognosis [4, 5]. Recently, thymic carcinoids have been reclassified as neuroendocrine carcinomas, and evidence suggests that these tumors form part of a continuous spectrum ranging from well-differentiated neuroendocrine carcinomas to small cell carcinomas [6–9]. We report here two new cases of carcinoid tumors of the thymus associated with Cushing’s syndrome and review the literature on this rare clinical condition.


   Case reports
Top
 Abstract
 Introduction
 Case reports
Comment
 References
 
The first patient, a 33-year-old woman, was referred to the University Hospital of Geneva because of Cushing’s syndrome. Her symptoms had progressively worsened over the previous 2 years and were characterized by muscular weakness, fatigue, and mild leg edema. On physical examination, she presented with a moon face, acne, oily skin, and easy bruising. Laboratory values disclosed a serum adrenocorticotropin (ACTH) level of 15.9 pmol/L (reference range: 2.0 to 12.0 pmol/L) and a free urinary cortisol level of 335 nmol/24 hours in the 24-hour urine collection (reference range: 30 to 105 nmol/24 hours). The elevated ACTH level excluded the presence of a primary adrenal secretion of cortisol. Therefore, a dexamethasone suppression test was performed, which showed free plasma cortisol levels of 650 nmol/L before the suppression test and of 627 nmol/L and 661 nmol/L after 1 mg and 8 mg, respectively, of oral dexamethasone administration (reference range: 120 to 620 nmol/L). The absence of cortisol suppression was highly suggestive of an ectopic secretion of ACTH. This suspicion was further reinforced by the absence of pituitary anomaly on brain magnetic resonance imaging and by the absence of an ACTH gradient between central and peripheral measurements during the inferior petrosal sinus catheterization, either before or after corticotropin-releasing hormone (CRH) stimulation. A thoracoabdominal computed tomographic scan (CT) revealed a 2-cm left paracardiac mass compatible with a tumor originating in the thymus (Fig 1). Although this mass did not show up on an octreotide scan performed 5 days later, the evidence suggested the presence of ectopic secretion of ACTH, and a small left anterior thoracotomy was performed to remove the thymus (Fig 2). Histologic examination revealed a carcinoid tumor of the thymus surrounded by a fibrotic capsule and expressing ACTH, chromogranin A, and synaptophysin on immunostaining. Nuclear pleomorphism, mitosis, and necrosis were absent (well-differentiated or grade I neuroendocrine carcinoma). The resection margins were free of tumor, and no capsular invasion was detected microscopically. The free plasma cortisol level decreased to less than 27.6 nmol/L 2 days after surgery, and the plasma ACTH level and the 24-hour free urinary cortisol level measured 1 month after surgery were within normal ranges. No adjuvant therapy was administrated. At 10-month follow-up, the patient is doing well, her clinical symptoms have resolved, and no signs of recurrence have been detected on chest CT. The free urinary cortisol level remains within the normal range.



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  		Fig 1. Computed tomographic scan of the chest showing a carcinoid tumor of the thymus (arrow).

 


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  		Fig 2. Surgical specimen showing a well-delimited carcinoid tumor of the thymus. The hemorrhagic gross appearance is typical of this tumor and is useful in the differential diagnosis with thymoma.

 
The second patient, a 38-year-old woman, was referred to the Toronto General Hospital with a 4-year history of intermittent and progressively worsening edema of the face, hands, arms, and legs. The patient also described weight gain and easy bruising. She had a previous history of hyperthyroidism at the age of 24 that was treated with radioiodine, and she was currently on thyroid replacement therapy. After a thorough examination, the urine and serum free cortisol levels were found to be elevated (1,209 nmol/24 hours and 1,258 nmol/L, respectively) and failed to be suppressed with low and high doses of dexamethasone. At the same time, the serum ACTH level was increased (28.4 pmol/L), and the blood potassium level was low (2.1 mmol/L). A magnetic resonance imaging scan of the brain revealed a decreased enhancement of the anterior pituitary gland compatible with a diffuse adenoma; however, the dexamethasone suppression test was negative, and no visual field defect was observed. Therefore, a thoracoabdominal CT was performed, and a left anterior mediastinal mass of 1.5 cm in diameter was demonstrated.

A median sternotomy was performed, and the thymus with its tumor was removed. On histologic examination, a carcinoid tumor of the thymus was demonstrated. In contrast to the previous case, moderate nuclear and cellular pleomorphism was seen with occasional mitotic figures and infiltration of the tumoral capsule (moderately differentiated or grade II neuroendocrine carcinoma). Immunohistochemistry revealed synaptophysin and chromogranin A positivity, but it remained negative for ACTH. No adjuvant therapy was administrated. Three years later, the patient presented with recurrent symptoms and a mediastinal mass in the right anterior mediastinum. The mass was resected again. A recurrent thymic carcinoid tumor infiltrating peritumoral adipose tissue was diagnosed and stained positive for ACTH. Resection margins were histologically free of tumor. Postoperative radiotherapy was administrated, and the patient is alive without recurrence 3 years later.


   Comment
Top
 Abstract
 Introduction
 Case reports
 Comment
References
 
Incidence
Ectopic ACTH-secreting tumors are rare neoplasms that were first described by Brown in 1928 [10]. These tumors occur primarily in the lung, but they have been observed in other organs such as the pancreas, esophagus, and stomach [11]. In the thymus, neuroendocrine carcinomas account for approximately 2% to 4% of all anterior mediastinal tumors, and they may be associated with Cushing’s syndrome or may form part of the multiple endocrine neoplasms type 1 syndrome [4, 12, 13]. Neuroendocrine carcinomas of the thymus associated with Cushing’s syndrome have been reported in 23 cases in the English literature since 1972 and form the basis of this report (Table 1). Before the first description of the entity in 1972, it is likely that an additional 10 to 20 cases of neuroendocrine carcinoma of the thymus associated with Cushing’s syndrome had been reported under another name [4, 27].


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  		Table 1. Thymic Carcinoid Associated With Cushing’s Syndrome Reported in the Literature Since 1972

 
Clinical features
Neuroendocrine carcinomas of the thymus associated with Cushing’s syndrome can occur at any age from 4 to 64 years, but they peak between the second and fourth decades of life. In contrast to thymic neuroendocrine carcinomas associated with multiple endocrine neoplasms type 1 syndrome, which occurred predominantly in men, thymic neuroendocrine carcinoma occurred as frequently in men as in women when associated with Cushing’s syndrome [3, 31, 32].

Although all patients in the literature presented with clinical features of Cushing’s syndrome, the severity and rapidity of onset varied. In some patients, symptoms occurred over a period of a few weeks and were primarily metabolic, whereas in others the physical signs of hypercortisolism were predominant [15, 21, 28, 30]. Cutaneous hyperpigmentation has been reported in four cases and is most likely due to a direct stimulation of melanocytes by corticotropin, although release of melanocyte-stimulating hormone by the tumor could also be a possible mechanism [18, 20, 21, 28, 30]. The time elapsed between the first clinical complaint and the diagnosis of thymic neuroendocrine carcinoma varied between 6 months and 8 years, with a mean of approximately 3 years among all reported cases [18, 30]. This variation in the time for diagnosis can be explained in part by the slow occurrence of the symptoms and by the periodic hormonogenesis of the tumor with intermittent secretion of ACTH, which renders the diagnosis more difficult [19, 23, 24].

Diagnosis
Cushing’s syndrome must be confirmed by elevated cortisol levels in the serum or in the 24-hour urine collection and must remain so despite low-dose dexamethasone suppression test. The presence of elevated ACTH levels excludes the possibility of an autonomous secretion of cortisol by an adrenal tumor. The major challenge resides in differentiating between a pituitary adenoma and an ectopic secretion of ACTH (Fig 3). Several biochemical tests have been developed over the last two decades and are based on the response rate of pituitary adenomas to stimulating or inhibiting agents, such as CRH, metyrapone, or dexamethasone. Traditionally, a drop in the 24-hour urine and plasma steroids of more than 50% of base line after 8 mg of oral dexamethasone suppression test indicates pituitary secretion of ACTH (Cushing’s disease). However, ectopic ACTH-secreting tumors have occasionally been suppressed by high-dose dexamethasone, which has led to inappropriate hypophysectomy when magnetic resonance imaging disclosed a pituitary abnormality as well [33]. Therefore, in order to improve the accuracy of the dexamethasone suppression test, several strategies have been proposed including the requirement of a greater suppression of plasma and urine steroids, its association with metyrapone or CRH stimulation test, intravenous infusion of dexamethasone (instead of oral administration), or administration of a higher dose of dexamethasone [34–36]. However, none of these methods has been accurate enough to definitively differentiate between a pituitary and an ectopic secretion of ACTH [37, 38].



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  		Fig 3. Algorithm for the diagnosis of patients with Cushing’s syndrome due to ectopic secretion of adrenocorticotropin. (ACTH = adrenocorticotropin; CT = computed tomographic scan; MRI = magnetic resonance imaging.)

 
Over the last decade, inferior petrosal sinus catheterization with concomitant measurements of central and peripheral ACTH levels has been shown to be the most efficient approach [39, 40]. Indeed, if the gradient between the inferior petrosal sinus and the peripheral vein samplings is equal to or greater than 2 before CRH stimulation and equal to or greater than 3 after CRH stimulation, the sensitivity and specificity of the test reaches almost 100% [40, 41]. False-negative results may be due to a hypoplastic or plexiform inferior petrosal sinus with anomalous drainage from the pituitary, and false-positive results have been described in patients with an ectopic secretion of both ACTH and CRH [33, 42]. Hence, given the accuracy of these results, some authors have proposed performing inferior petrosal sinus catheterization as an initial step in the differential diagnosis of Cushing’s syndrome (option 2 in the algorithm presented in Fig 3) [33]. In contrast, other investigators, considering the invasiveness of the procedure and the potential risk of brain injury, reserve petrosal sinus catheterization for the assessment of patients in whom the results of biochemical tests or subsequent pituitary magnetic resonance imaging were equivocal (option 1 in the algorithm presented in Fig 3) [41].

Ectopic ACTH-secreting tumors can be exceedingly small and may not be depicted on CT [23, 33]. Therefore, if an ectopic source is highly suspected, chest CT with 5-mm slices is recommended and should be followed by an octreotide radio-labeled scan if it remains negative [30, 33, 43]. Carcinoid tumors have been shown to express somatostatin receptors and thus can be highlighted with the somatostatin analogue octreotide in more than 80% of cases [44]. Occasionally, technetium-99m methoxyisobutylisonitrile, an unspecific agent reflecting metabolic activity, has also been used to depict ACTH-producing tumors [30, 45]. Nevertheless, one should not forget that the sensitivity of these tests is not perfect, and they should be repeated in a close follow-up if they are negative.

Pathology
Neuroendocrine carcinomas of the thymus vary from less than 2 cm to more than 10 cm in greatest diameter [18, 21]. They are of soft consistency and appear gray-white to brownish on cut surface [46]. The tumors are usually well circumscribed, though invasion of the surrounding structures such as the pleura, lung, pericardium, or innominate vein can occasionally be observed [5, 20, 24, 47, 48].

In order to simplify and make uniform the nomenclature, carcinoid tumors have been reclassified according to specific criteria (such as the mitotic activity and the presence of necrosis or cytologic atypia) as grade I neuroendocrine carcinoma (previous carcinoid tumors/well-differentiated neuroendocrine carcinoma), grade II neuroendocrine carcinoma (previous atypical carcinoid/moderately differentiated neuroendocrine carcinoma), and grade III neuroendocrine carcinoma (previous large cell neuroendocrine and small cell carcinomas) [6, 49]. The majority of neuroendocrine carcinomas occurring in the thymus display atypical features such as increased mitotic activity, nuclear pleomorphism, and areas of necrosis, and they should therefore be referred to as atypical carcinoids or as grade II neuroendocrine carcinomas [8, 29, 47, 50].

Well-differentiated or grade I neuroendocrine carcinomas of the thymus, ie, with no sign of atypia, as reported in our first patient, are extremely rare [29]. Indeed, in contrast to neuroendocrine tumors of the lung, progressive malignant transformation is frequently observed in thymic neuroendocrine tumors and results in a lower degree of tumor differentiation at the time of diagnosis. Moran and Suster [7] have recently reported on 11 cases of primary thymic neuroendocrine carcinoma that combined features ranging from well-differentiated (carcinoid) or moderately differentiated (atypical carcinoid) to poorly differentiated carcinoma (small cell carcinoma). The authors concluded that this finding may explain the poor prognosis observed in these patients and may further reinforce the notion that carcinoid tumors and small cell carcinoma represent different parts of the same tumor entity [51].

Although unusual features, such as melanin pigment, spindle cell features, oncocytic cytoplasm, or mucin-rich stroma, have been described in thymic neuroendocrine carcinoma, none of them has been shown to adversely change the prognosis [22, 52–55]. In addition, tumors with a higher grade of malignancy or with sarcomatoid differentiation have not been shown to have a different outcome, probably because of the relatively small number of cases [29, 56, 57].

Immunohistochemical analysis usually shows positive staining with chromogranin A and synaptophysin, which are useful tools for the diagnosis of neuroendocrine carcinoma of the thymus [46]. Adrenocorticotropin staining is usually positive, although its presence does not necessarily correlate with the clinical features. Adrenocorticotropin may stain positive in the absence of Cushing’s syndrome, and conversely, negative ACTH staining does not preclude the diagnosis of Cushing’s syndrome, as observed in our second patient [12, 58].

Treatment
Surgery is the therapy of choice for neuroendocrine carcinoma of the thymus. Aggressive local resection of these tumors usually includes the entire thymus and perithymic fat. Hence, a median sternotomy is indicated in most cases of neuroendocrine carcinomas of the thymus, and a limited approach should be avoided. Occasionally, when the tumor is large and locally extensive yet apparently resectable, the addition of an anterior (or posterolateral) thoracotomy should be considered for better exposure of the involved hemithorax. An aggressive resection may include pericardium, adherent lung, mediastinal nodes, and occasionally a phrenic nerve. The role of adjuvant or neoadjuvant radiotherapy, chemotherapy, or both has not been adequately assessed because of the low number of cases. Nevertheless, postoperative radiotherapy may be helpful in preventing local recurrence after excision of an invasive carcinoma [29].

Because of the prolonged high serum cortisol level, pituitary secretion is suppressed. Therefore, parenteral glucocorticoid substitution therapy is indicated during the surgical procedure. A dose of 100 mg hydrocortisone should be given intravenously with induction of anesthesia and followed by three intravenous injections of 100 mg hydrocortisone every 6 hours [59, 60]. After the first 24 postoperative hours, oral corticosteroids should be started and tapered by 50% each day until the patient is taking 5 mg prednisone daily [60]. If the patient has postoperative complications or manifestations of hypoadrenalism during tapering, the dosage of corticosteroids should be increased. Once the pituitary secretion has recovered, corticosteroids can be stopped [60, 61].

Prognosis
Despite aggressive therapy, these tumors carry a poor prognosis, and most patients present local recurrence or metastasis within 5 years after surgery and will die within 10 years [2, 5, 8].

Neuroendocrine carcinomas associated with Cushing’s syndrome have been reported to be more aggressive in the lung and in the thymus [4, 33]. At the time of this report, accordingly, we noted that among the 25 cases reported in the literature since 1972, 9 patients had died and 7 were alive with recurrence at the time of report. Only 6 patients were alive without recurrence at the time of report, but their follow-ups ranged from 10 months to 2 years only (Table 1). It must be emphasized, however, that most of these tumors were larger than 5 cm, infiltrated the thymic capsule, or had metastasized to proximal lymph nodes by the time of surgery. In addition, in several patients, the tumor could not be resected or was incompletely resected because of extensive mediastinal infiltration. Therefore, the advent of radiologic and nuclear imaging and more accurate workup should help to diagnose these tumors at an earlier stage and thus should improve long-term outcome in the future. Postoperative follow-up with serum and urine free cortisol as well as with regular chest CT or magnetic resonance imaging is also recommended because of the risk of recurrence.


   References
Top
 Abstract
 Introduction
 Case reports
 Comment
 References
 

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