| Abstract|| |
Thymomas constitute majority of the thymic neoplasms. In contrast, neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) of thymus are extremely rare. Thymic carcinoids may present rarely with Cushing's syndrome due to the ectopic production of adrenocorticotropic hormone (ACTH). Recognition of this association is imperative for appropriate management of patients. We describe three cases of rare atypical carcinoid tumor (neuroendocrine carcinoma) of the thymus.
Case 1, of a 26-year-old man presenting with Cushing's syndrome, case 2 - a 23-year-old female with Cushingoid features, and Case 3 - a 39-year-old man complaining of progressively worsening dyspnea. Computed tomography (CT) scans of chest in all three patients revealed anterior mediastinal mass. Excision of tumors and histological examination of the three tumors showed a carcinoid tumor with nuclear pleomorphism, increased mitotic activity and focal necrosis. The features suggested a diagnosis of atypical carcinoid tumor in all the three cases. The tumor cells in Cases 1 and 2 showed focal immunohistochemical staining for ACTH.
Atypical carcinoid (neuroendocrine carcinoma, well-differentiated and moderately-differentiated) of the thymus is a rare thymic tumor which carries a worse prognosis compared to thymoma and requires aggressive therapy. Hence, an accurate diagnosis is essential.
Keywords: Atypical carcinoid, cushing′s syndrome, neuroendocrine carcinoma, thymus
|How to cite this article:|
Arora R, Gupta R, Sharma A, Dinda AK. Primary neuroendocrine carcinoma of thymus: A rare cause of Cushing's syndrome. Indian J Pathol Microbiol 2010;53:148-51
|How to cite this URL:|
Arora R, Gupta R, Sharma A, Dinda AK. Primary neuroendocrine carcinoma of thymus: A rare cause of Cushing's syndrome. Indian J Pathol Microbiol [serial online] 2010 [cited 2013 May 23];53:148-51. Available from: http://www.ijpmonline.org/text.asp?2010/53/1/148/59210
| Introduction|| |
Thymic carcinoid tumors are rare neoplasms accounting for about two per cent of all carcinoid tumors.  In majority of the cases, thymic carcinoids are atypical carcinoid tumors on histomorphological appearance.  Thymic carcinoid may rarely be the cause of Cushing's syndrome due to ectopic ACTH production.  Such tumors may escape initial detection due to the location and usually small size. In contrast to the more common thymic tumors, including thymoma, atypical carcinoids tend to have an aggressive clinical course and worse prognosis and hence their recognition is essential.  Recently, authors reporting cases of this unusual tumor have suggested the use of term 'neuroendocrine carcinoma' rather than atypical carcinoid.  Only a few reports of thymic carcinoid from this subcontinent were found in available literature. ,,
We report three cases of neuroendocrine carcinoma (atypical carcinoid tumor) of the thymus, two of which presented with Cushing's syndrome. This rare entity is briefly discussed with review of the relevant literature.
| Case Reports|| |
A 26-year-old male patient presented with significant weight gain and weakness. Physical examination showed skin pigmentation, moon-like facies, central obesity and buffalo hump in the upper back. He was normotensive (blood pressure 130/84mmHg). Laboratory investigations revealed hyperglycemia (fasting blood glucose 9.2mmol/L, normal range 3.9-6.1mmol/L), normal levels of serum electrolytes and thyroid hormones. The basal serum cortisol level was 41.1µg/dl (normal range 7-22µg/dl) at 8.00am and circadian rhythm was absent. Dexamethasone, eight mg, failed to suppress the 24-hour urinary free cortisol, UFC (UFC 3753µg/24h, normal range 20-90µg/24h). Plasma ACTH levels were markedly raised to 620pg/ml (normal range 12-78pg/ml). These features suggested a diagnosis of ACTH-secreting non-pituitary tumor. CT scan showed an anterior mediastinal (thymic) mass measuring six cm in diameter. There was no infiltration of adjacent structures or pleural effusion. The patient underwent resection of the mediastinal mass.
A 23-year-old female presented with Cushingoid facies. Investigations showed hypercortisolism with raised serum ACTH levels and negative dexamethasone suppression test similar to Case 1. CT scan revealed an anterior mediastinal mass measuring two cm in greatest dimension. A thymectomy with excision of the tumor was performed.
A 39-year-old man presented with history of gradually worsening respiratory difficulty for eight months. There were no associated complaints of cough, hemoptysis, palpitations or any significant past medical or surgical history. Radiological investigations, including CT scan, showed a large mediastinal mass measuring 12 cm in size compressing, but not infiltrating the adjacent structures. Biochemical investigations including serum cortisol and ACTH levels were within normal limits. The patient underwent thymectomy with excision of the tumor.
Gross and microscopic features were similar in all three cases, except for the size of the tumor. The tumor measured 5x3x3 cm in Case 1, 1.2x1.0.3 cm in Case 2 and 12x9.2x5.8 cm in Case 3.
Multiple sections from the three specimens showed tumor composed of cells arranged in sheets, nests, ribbons and festoons. The tumor cells were monomorphic with moderate amount of granular cytoplasm, round nuclei and finely dispersed chromatin [Figure 1]a, b. There was mild nuclear pleomorphism and mitotic activity ranging between 2-8/ 10 high power fields in the three cases [Figure 1]c. Focal hemorrhage and necrosis was also noted. Foci of hemosiderin pigment deposition and calcification were noted in case 1 [Figure 1]d. An occasional rosette formation was seen in cases 1 and 2.
On immunohistochemistry, the tumor cells showed strong cytoplasmic positivity for chromogranin and synaptophysin and dot-like positivity for cytokeratin (AE1/AE3) in all three cases [Figure 2]a, b, c. The tumor cells were negative for leukocyte common antigen, CD 20 (B-cell marker) and CD3 (T-cell marker). Tumor cells in cases 1 and 2, in addition, showed focal cytoplasmic immunoreactivity for ACTH [Figure 2]d.
A final diagnosis of atypical thymic carcinoid was rendered in all the three cases. The patients have been doing well at follow-up of five months in case 3, 10 months in case 2 and 11 months in case 1.
| Discussion|| |
Carcinoid tumor in thymus is a rare occurrence and accounts for about two per cent of all carcinoid tumors.  On an extensive literature search, only a few cases of thymic carcinoid tumors reported from this subcontinent were found. ,, Rarely, carcinoid tumors of thymus may be associated with Cushing's syndrome due to ectopic ACTH production. Such thymic carcinoids, which are associated with Cushing's syndrome occur over a wide age range of four to 64 years and show no gender predilection. The most common manifestations of the tumors producing ectopic ACTH include Cushingoid features. However, hypertension, edema, severe hypokalemia and myasthenia are more common in ectopic ACTH-producing tumors than in Cushing disease.  The diagnosis of ectopic ACTH production relies on the negative suppression test using dexamethasone, corticotrophin releasing hormone or metyrapone.  If an ectopic source of ACTH secretion is suspected based on the negative dexamethasone suppression test, then X-ray and CT scan of the chest are recommended to detect small thymic carcinoids.  In the present series, Case 2 demonstrated such a case where a small thymic tumor was the source of ectopic ACTH production.
Carcinoid tumors, unlike thymoma, show histological features of a neuroendocrine tumor characterized by solid nests, ribbon and festoon, rosette-like glands and 'balls' of cells with central necrosis. Calcification, marked vascularity and lymphovascular embolization are frequent.  Immunohistochemical methods reveal positive staining for cytokeratin and neuroendocrine markers like synaptophysin, chromogranin and neuron-specific enolase. In addition, numerous bioactive amines and peptides including ACTH, serotonin and insulin have been demonstrated.  In the present series, two patients presented with Cushing's syndrome and thymic tumors in both these cases showed positive staining for ACTH.
The neuroendocrine tumors of thymus have earlier been divided using the classification proposed by Travis et al. for neuroendocrine lung tumors, i.e. typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma.  Applying the same criteria, all three tumors in the present series were categorized as atypical carcinoid tumors. The exact proportion of atypical carcinoid among thymic carcinoid tumors is not known, since only a few reports have categorized their tumors as typical or atypical.  However, it has recently been argued that the clinical behavior of thymic carcinoids follow a more aggressive course as compared to similar tumors at other locations.
For mediastinal carcinoids, a nomenclature proposed by Rosai et al included carcinoid grade I (well differentiated, equivalent to conventional carcinoid); carcinoid grade II (moderately differentiated, equivalent to atypical carcinoid); and carcinoid grade III (poorly differentiated, equivalent to small cell carcinoma). Later, Wick and Rosai  suggested the use of the term 'neuroendocrine carcinoma' in place of carcinoid for mediastinal neuroendocrine tumors and this has been supported by other authors. , The clinical behavior of neuroendocrine tumors of thymus correlates closely with the histological degree of differentiation: disease-free survival at five years has been reported to be 50% for well-differentiated, 20% for moderately differentiated and zero per cent for poorly differentiated tumors. 
The important differential diagnoses for thymic neuroendocrine tumors include thymoma, paraganglioma, parathyroid adenoma or carcinoma, medullary carcinoma of thyroid and lymphoma. Thymoma, especially of spindle cell type, may exhibit foci with neuroendocrine appearance due to epithelial pseudo rosettes. Immunohistochemistry helps in the distinction since thymomas are negative for neuroendocrine markers.  Mediastinal paragangliomas are also composed of prominent organoid or neuroendocrine pattern. Paragangliomas lack significant cytologic atypia, mitotic activity, necrosis, vascular invasion and cytokeratin expression.  Ectopic parathyroid adenoma or carcinoma may enter the differential diagnosis; and can be diagnosed by the presence of cytoplasmic glycogen and expression of parathyroid hormones on immunohistochemistry.  Medullary thyroid carcinoma in an ectopic mediastinal location may also be confused with thymic neuroendocrine tumors. However, immunoreactivity for calcitonin and carcinoembryonic antigen would help to make the correct diagnosis. Diffuse large cell lymphoma may be a diagnostic consideration in tumors composed predominantly of diffuse sheets. The granular character of chromatin, eosinophilic granular cytoplasm, focal nesting pattern and non-reactivity for lymphoid markers would assist in ruling out this possibility. 
Surgical resection is the best therapeutic modality for thymic carcinoids. Chemotherapy and/or radiotherapy has been tried, especially for metastatic carcinoids with variable response rates of 30-60%.  Invasion of local structures is reported in 50% of thymic carcinoids and extra thoracic metastasis in 20-30%.  In the present report, none of the three cases showed any evidence of local infiltration by the tumor and have been doing well on follow-up.
| Conclusion|| |
Atypical carcinoid tumor (neuroendocrine carcinoma) of the thymus is a rare thymic neoplasm and may be the cause of ectopic secretion of adrenocorticotropin. Since the prognosis of neuroendocrine carcinoma is worse than thymoma, an accurate histopathological diagnosis is essential for management and prognostication of a given case.
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