Asian Cardiovasc Thorac Ann 2006;14:e30-e32
© 2006 Asia Publishing EXchange Ltd
Carcinoid Tumors of the Thymus
Suresh B Kale, MCh,
Devendra S Saksena, FACS,
Shrikant D Kole, MCh,
Yeshwant C Agnihotri, MCh
Department of Cardiovascular Thoracic Surgery, Bombay Hospital Institute of Medical Sciences, New Marine Lines, Mumbai, India
For reprint information contact: Denvendra S Saksena, MD Tel: 91 22 2215 0814 Fax: 91 22 2208 1313 Email: saksenad{at}bom3.vsnl.net.in, Department of Cardiovascular Thoracic Surgery, Bombay Hospital Institute of Medical Sciences, New Marine Lines, Mumbai 400 020, India.
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ABSTRACT
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Twenty-five cases of neuroendocrine carcinoma of the thymus associated with Cushing’s syndrome have been reported since 1972.1 We report two new cases of thymic carcinoid, one of which presented with Cushing’s disease. These patients were successfully treated and were asymptomatic at the time of first follow-up.
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INTRODUCTION
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Neuroendocrine carcinoma of the thymus accounts for 2% to 4% of all anterior mediastinal tumors and may be associated with Cushing’s syndrome or may form part of the multiple endocrine neoplasia type 1 syndrome.2 Mediastinal or thymic carcinoids are extremely rare and only a few small series have been reported in the literature.3 These are associated with endocrinopathies and carry a poor prognosis.4 Carcinoid of the thymus associated with Cushing’s syndrome is a rare disease with 25 reported cases in the literature since 1972. We report two new cases of thymic carcinoid, one of which presented in association with Cushing’s disease.
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CASE REPORT
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CASE 1
The first patient was a male, aged 40 years, referred from a secondary center, with a history of left-sided chest pain and generalized weakness for the past 1 month. A baseline electrocardiogram was obtained and was normal. The patient was not anemic. Respiratory system examination revealed a centrally placed trachea and limited air entry in the left mammary area. Biochemical investigations were in the normal range. Chest X-Ray revealed a homogeneous large anterior mediastinal mass extending into the left hemithorax. Computed tomography scan of the chest with contrast showed a well-differentiated solid lobulated mass with irregular margins at the junction of the heart and great vessels extending superiorly onto the anterior surface of the aortic arch and inferiorly along the left paracardiac border. The mass measured 11.6 cm antero-posteriorly and 11 cm transversely with punctate calcification. The trachea, carina, major bronchus, and lung parenchyma were normal, suggesting a solid thymoma. The abdomen including testicles, and nervous system examination were normal. The mass was approached through a standard median sternotomy. It was firm in nature, with a lobulated surface, measuring 12 cm x 10 cm, densely adherent to the pericardium along the left cardiac border and extending laterally to the hilum of the left lung.
Frozen section histopathology of the mass was obtained and was reported to be a small cell carcinoma. Near total excision of the mass was performed except for a small area around the hilum of the left lung, which could not be excised. Retrospectively tumor markers for beta HCG and alpha fetoproteins were checked and were found to be in the normal range. Ultrasonography of the abdomen and 99Tc MDP bone scan was normal. The thyroid profile was in normal limits. Paraffin block histopathology of the specimen proved it to be a neuroendocrine carcinoma of the thymus. The cells were medium sized, arranged in compact cohesive nests, with hyperchromatic nuclei and florid mitotic activity. Satellite nodules were present. The immunohistochemistry profile (Table 1
) was strongly positive for synaptophysin, neuron-specific enolase, and chromogranin A. In view of the residual mass along the left pulmonary hilum, the patient was subjected to chemotherapy post-surgery. He had three cycles of chemotherapy with cisplatin, adriamycin, and etoposide at an interval of 1 month each.
The patient presented with symptoms of breathlessness at the end of three months. A repeat computed tomography scan of the chest at the end of three cycles of chemotherapy was obtained. It showed a residual soft tissue mass of 9.8 cm x 12 cm in the left anterior mediastinum involving the hilum of the left lung. The growth of the residual mass to this size was rapid and progressive. He was operated five months later through a left posterolateral thoracotomy. The mass was excised in total along with a left pneumonectomy. The postoperative course was uneventful. The patient was subjected to radiotherapy and at the end of 3 months post surgery was free of symptoms.
CASE 2
A 58-year-old hypertensive male was referred as a case of suspected thymic carcinoid with coronary artery disease for further management. The patient was admitted with a history of left precordial pain, palpitations and sweating of recent onset. He was diagnosed to have ischemic heart disease with two-dimensional echocardiography evidence of wall motion abnormalities and a left ventricular ejection fraction of 50%. Controlled stress test was positive for provokable ischemia. One month later he had complaints of generalized weakness, facial mooning, weight loss of 4 to 5 kg, and proximal muscle weakness (difficulty in getting up from a squatting position). On examination, pedal edema, facial mooning, knuckle pigmentation, buffalo hump, and acne were evident. The fundus examination was normal. Thyroid profile and biochemical investigations were normal. Basal cortisol levels were very high. Chest X-Ray was normal. Magnetic resonance imaging of the brain did not show any pituitary gland abnormalities. The patient was subjected to a high dose dexamethasone suppression test. The cortisol and ACTH levels (midnight, basal) did not show suppression with high-dose dexamethasone and hence an ectopic source for the ACTH secretion was considered. Computed tomography scan of the abdomen and pelvis was normal. Computed tomography scan of the chest showed a nodular thymic mass of 4 cm x 5 cm, extending between the superior vena cava and the left brachiocephalic vein anterior to the ascending aorta and aortic arch, infiltrating the pericardium inferiorly. Bilateral multiple lung nodules were also present. The mass was not amenable to biopsy. Proximal muscle weakness was investigated with electromyography and nerve conduction velocity studies. These confirmed Cushing’s myopathy with an element of added sensorimotor neuropathy. In view of his angina and positive stress test, coronary angiography was performed. Significant two-vessel disease (left anterior descending and right coronary artery lesion) with good left ventricular ejection fraction was found.
The patient was operated on through a standard median sternotomy. A thymic mass of about 6 cm x 5 cm was hard to firm in consistency and involved the pericardium, perithymic tissues and the lower part of the left brachiocephalic vein. It extended laterally up to the superior vena cava. Total excision of the mass was done. The inferior border of the left brachiocephalic vein was excised and reconstructed primarily. A two-vessel beating heart coronary artery bypass grafting was carried out. Both the lungs exhibited multiple nodules and were left alone. The postoperative course was uneventful. Microscopic examination of the mass showed predominantly small round cells in compact groups with hyperchromatic nuclei and florid mitotic activity. Numerous melanin deposits were evident. The immunohistochemistry profile was strongly positive for synaptophysin, chromogranin A, and neuron-specific enolase.
The patient’s cortisol levels were high in the postoperative period and adrenolytic ketoconazole was started. The patient developed severe depression a week after starting ketoconazole therapy and the drug was withdrawn. The patient was asymptomatic at follow-up 3 months later. Repeat chest X-Ray performed at the end of 3 months showed bilateral minimal pleural effusion. The lung parenchyma was normal. The cortisol levels were high normal.
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DISCUSSION
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The thymus is considered the principal origin for primary mediastinal carcinoid tumors. Thymic carcinoid tumors may present with a variety of clinical onsets, behave as malignant tumors and have a prognosis related to how radical the surgical resection is. These tumors can be either asymptomatic or part of the multiple endocrine neoplasia syndrome and can produce endocrinopathy, especially Cushing’s syndrome. A metastasis, especially from a bronchopulmonary carcinoid tumor must be formally excluded.3 Ectopic ACTH-secreting tumors are rare neoplasms that were described by Brown in 1928.5 They primarily occur in the lungs, but have also been seen in organs such as the pancreas, esophagus, and stomach.6 They occur at any age between 4 and 64 years, peaking between the second and fourth decades. They are seen as often in men as in women as compared to neuroendocrine tumors of the thymus associated with multiple endocrine neoplasia type 1, where male sex predominates.5
The severity and rapidity of onset of Cushing’s syndrome in our case was over a period of a few weeks, with physical signs of hypercortisolism. Inferior petrosal sinus catheterization with simultaneous measurement of central and peripheral ACTH levels has been shown to be the most efficient procedure,7 but was not done in our case as it is invasive, with a potential risk of brain injury.8 Computed tomography of the chest showed the thymic mass more evidently and hence a radiolabelled octreotide scan was not obtained. Neuroendocrine carcinomas of the thymus vary from 2 cm to 10 cm in size (present case 11.6 cm), are soft in consistency, and well circumscribed, although our cases exhibited gross infiltration into surrounding tissues suggesting malignant behavior. Both cases displayed increased mitotic activity and nuclear pleomorphism. These tumors exhibit combined features of a well-differentiated carcinoma to poorly differentiated carcinoma, which explains the poor prognosis in these patients.
Surgery is the most effective treatment for neuroendocrine carcinoma of the thymus and complete resection offers the best hope for long-term survival.4 Aggressive local resection along with perithymic fat and other involved structures is indicated. A left pneumonectomy in the first patient and excision of the inferior border and reconstruction of the left brachiocephalic vein in the second patient of our series indicates how radical the surgery is required to be. If the tumor is large, a thoracotomy is highly indicated to facilitate en bloc tumor excision. Steroid supplementation should be considered in the perioperative period if the patient presents with Cushing’s disease. The second patient in our study had increased cortisol levels probably from lung metastases. Chemotherapy has a limited role. Radiotherapy may benefit those after surgical excision and failed chemotherapy.
Despite aggressive therapy, these tumors carry a poor prognosis and most patients present with local recurrence or metastasis within 5 years after surgery and will die within 10 years.4,3 As a result of the risk of recurrence, postoperative follow-up with measurement of serum and urine-free cortisol levels as well as regular chest computed tomogram or magnetic resonance imaging is also recommended.5
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REFERENCES
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- Economopoulos GC, Lewis JW Jr, Lee MW, Silverman NA. Carcinoid tumors of the thymus. Ann Thorac Surg 1990; 50:58–61.[Abstract]
- Duh QY, Hybarger CP, Geist R, Gamsu G, Goodman PC, Gooding GA, et al. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 1987; 154:142–8.[Medline]
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- de Herder WW, Uitterlinden P, Pieterman H, Tanghe HL, Kwekkeboom DJ, Pols HA, et al. Pituitary tumour localization in patients with Cushing’s disease by magnetic resonance imaging. Is there a place for petrosal sinus sampling? Clin Endocrinol (Oxf) 1994; 40:87–92.[Medline]
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- Imura H, Matsukura S, Yamamoto H, Hironosuke H, Hirata Y, Nakai Y. Studies on ectopic ACTH-producing tumors. II. Clinical and biochemical features of 30 cases. Cancer 1975; 35:1430–7.[Medline]
- Miller DL, Doppman JL. Petrosal sinus sampling: technique and rationale. Radiology 1991; 178:37–47.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
