46 Pantula et al Neuroendocrine carcinoma of thymus Case report

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Neuroendocrine carcinoma of thymus associated with cushing’s syndrome – A case report Narasingarao Pantulaa, MCh, Ramesh Jayanthyb, DM, Vasani Kannana, BS, Satish Kumar Missulac, DA Department of Cardiothoracic Surgerya Department of Endocrinologyb, Yashoda Hospitals, Somajiguda, Hyderabad, India and Anaesthesiologyc Kamineni Wockhardt Hospitals, King Koti, Hyderabad, India Abstract Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome is a rare disease. These tumors behave aggressively with a tendency to invade adjacent structures. Majority of patients present with local recurrence of metastasis within five years after surgery. Surgical resection remains the treatment of choice as adjuvant radiotherapy and/or chemotherapy is controversial. We report a case of neuroendocrine carcinoma of thymic origin associated with ectopic adrenocorticotropin (ACTH) production causing Cushing’s syndrome and present a brief review of literature on this rare clinical condition. (Ind J Thorac Cardiovasc Surg 2010; 26: 46-48) Key words : Tumor, Chemotheraphy, Metastasis Case report A 14-year-old boy presented with a history of vomiting, severe headache, loss of appetite of 1 month duration. Parents noted that the child was gaining weight for the past 2 years. The physical examination revealed moon face, buffalo hump, central obesity and hyper pigmentation of the knuckles suggestive of Cushing’s syndrome. His heart rate was 118 per minute with a blood pressure recording of 130/90mmHg. Biochemical evaluation disclosed very high levels of plasma cortisol {50.84µg/dL (normal range 5-25µg/dl)} and serum ACTH {118pg/ml (normal range (6-76pg/ dl)}. A low dose Dexamethasone suppression test revealed free plasma cortisol level of 28.8µg/dl confirming the diagnosis of Cushing’s syndrome. The presence of high levels of ACTH ruled out the primary adrenal secretion of cortisol. A high dose Dexamethasone suppression test was performed, which did not suppress the cortisol secretion (Cortisol of <50% Address for correspondence: Dr. Narasingarao Pantula Consultant Cardiothoracic Surgeon, Kamineni Wockhardt Hospitals, Hyderabad - 500001, India Tel: 91-40-55924444 Fax: 91-40-55924242 E-mail: [email protected] © IJTCVS 097091342610310/54 CR Received - 10/07/06; Review Completed - 05/10/08; Accepted - 23/12/09.

of baseline values) and the cortisol level was 27.64µg/ dl. This was highly suggestive of an ectopic secretion of ACTH. A magnetic resonance imaging of the brain showed no mass lesion in the pituitary gland excluding the pituitary origin of high levels ACTH, which further reinforced the possibility of ectopic secretion of ACTH. A Computed Tomography (CT) scan of the chest (Fig. 1) revealed a mass in the anterosuperior mediastinum measuring about 7.0 × 5.0 cms. The lung parenchyma and bronchi were free of mass lesions. CT scan of the abdomen revealed normal study of liver, pancreas, spleen and kidneys. All the above investigations were suggestive of an ectopic secretion of ACTH from the mediastinal mass and surgical resection was planned. A median sternotomy was performed and was extended into the left hemithorax via third intercostal space to facilitate the en-bloc resection of the tumor including the left and right lobe of the thymus along with a satellite mass and the adipose tissue surrounding it, excepting the phrenic nerve which was preserved. The mass was measuring 6.5 × 5.0 × 4.0 cms and the cut section showed well-circumscribed lesion with grey brown areas with areas of necrosis and calcification. The tumor showed an extra capsular invasion into the surrounding adipose tissue. Hematoxylin & Eosin stained sections of the tumor (Fig. 2A) showed cells arranged in nesting pattern separated by fibrovascular

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Fig. 1. Computer tomogram of chest showing anterosuperior mediastinal mass.

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septa with nuclear pleomorphism and frequent mitoses. Immunohistochemistry (Fig. 2B) of the tumor cells stained positive for chromogranin. The lymph nodes were negative for evidence of tumor. These findings were confirmatory of grade II neuroendocrine carcinoma of mediastinal origin. During the perioperative period, patient was started on corticosteroids to prevent adrenal insufficiency. Patient made an uneventful postoperative recovery. Plasma Cortisol levels measured on the 5th postoperative day were significantly low (0.688µg/dl) confirming the successful removal of the source of ectopic ACTH. Patient received 4500 cGy of radiation to the chest in view of capsular invasion and the presence of a satellite mass. He also received chemotherapy with gemcitabine along with carboplastin (6 cycles). At one year follow up patient presented with features suggestive of raised intracranial tension with papilledema. Contrast enhanced CT of the brain revealed multiple metastases. However, CT chest revealed no evidence of local recurrence. Another course of chemotherapy with ifosfamide and etoposide (6 cycles) was given. Further follow up at 3 years revealed metastases to iliac bone. He was offered palliative treatment with bisphosphonates. Discussion

Fig. 2A. Hematoxylin & Eosin stained sections (H&E X10) of the tumor showing nested growth pattern.

Fig. 2B. Immunohistochemistry using antibody chromogranin.

Neuroendocrine carcinomas (carcinoids) of the thymus associated with Cushing’s syndrome are rare, histologically diverse neoplasms with an unpredictable clinical behavior1. They represent approximately 4% of all mediastinal tumors and occur between the ages of 4 years to 64 years old, but they peak between second and fourth decades of life2. They have a predilection for men. These neoplasms can either be asymptomatic, associated with symptoms related to local growth, or part of a MEN syndrome. Almost 50% of these tumors are associated with endocrinopathies, namely Cushing’s syndrome (33%), or multiple endocrine neoplasia (MEN) type I (19% to 25%) or MEN type II, and others3, 4. Localization of an ACTH secreting tumor can sometimes be challenging. A computerized tomography, MRI and an octreotide scan may be required to screen for ACTH-secreting tumors2. These tumors behave aggressively with invasion to adjacent mediastinal structures, local recurrence or metastasis1, 3, 5. Histologically neuroendocrine carcinomas have been classified according to specific criteria (such as the mitotic activity and the presence of necrosis or cytologic

48 Pantula et al Neuroendocrine carcinoma of thymus

atypia) as grade I (well-differentiated), grade II (moderately differentiated) and grade III (large cell carcinoma and small cell carcinomas). 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 grade II neuroendocrine carcinomas or atypical carcinoids2. Surgical resection is the treatment of choice. En-bloc resection of the tumor including the pericardium, lung, great vessels or all of these is recommended1-5. The role of adjuvant radiotherapy, chemotherapy, or both has not been adequately assessed1,3. Postoperative radiation therapy should be considered in patients with capsular invasion to prevent local recurrence. There are no standard regimens of chemotherapy1,3. Despite aggressive therapy, these tumors carry a poor prognosis. Chaer et al reported 51% and 27% survival at 3 and 5 years respectively. The survival was worse in tumors accompanied by an endocrinopathy4. In view of the risk of recurrence, aggressive follow up with regular contrast enhanced CT of chest along with Octreotide scintigraphy and estimation of biochemical marker chromogranin A is recommended3, 6. As described in the literature, the histopathological and immunohistochemistry findings in our patient were characteristic of grade II neuroendocrine carcinoma of the thymus, which is the commonest variety. Despite

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radiotherapy and chemotherapy, our patient developed metastases to brain and iliac bone reaffirming the aggressive nature of these tumors. These findings are consistent with the analysis of Gal et al who reported that neither chemotherapy nor radiotherapy leads to differences in survival. Adjuvant therapy may offer local disease control, it is not effective in eradicating tumor, nor does it prevent the development of recurrence or metastases1. References 1. Gal AA, Kornstein MJ, Cohen C, Duarte IG, Miller JI, Mansour KA. Neuroendocrine tumors of the thymus: a clinicopathologic study. Ann Thorac Surg 2001; 72: 1179–82. 2. de Perrot M, Spiliopoulos A, Fisher S, Totsch M, Keshavjiee S. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome. Ann Thorac Surg 2002; 73: 675–81. 3. Filosso PL, Ruffini E, Oliaro A, Papalia E, Donati G, Rena O. Long-term survival of atypical bronchial carcinoids with liver metastases, treated with octreotide. Eur J Cardiothorac Surg 2002; 21: 913–17. 4. Chaer R, Massad MG, Evans A, Snow N J, Geha AS. Primary Neuroendocrine Tumors of the Thymus. Ann Thorac Surg 2002; 74: 1733–40. 5. de Montpr'e ville VT, Macchiarini P, Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg 1996; 111: 134–41. 6. Dutta R, Kumar A, Jindal T, Mathur S R. Neuroendocrine carcinoma of the thymus gland with sternal invasion. Interact CardioVasc Thorac Surg 2009; 8: 694–96.