Ann Thorac Surg 2006;81:366-368
© 2006 The Society of Thoracic Surgeons
Case report
ACTH Secreting Thymic Carcinoid Associated With Multiple Endocrine Neoplasia Type 1
Motoki Yano, MD, PhD
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,
Ichiro Fukai, MD, PhD,
Yoshihiro Kobayashi, MD, PhD,
Kotaro Mizuno, MD, PhD,
Akimitsu Konishi, MD, PhD,
Hiroshi Haneda, MD,
Eriko Suzuki, MD,
Katsuhiko Endo, MD,
Yoshitaka Fujii, MD, PhD
Department of Surgery II, Nagoya City University Medical School, Nagoya, Aichi, Japan
Accepted for publication July 29, 2004.
* Address correspondence to Dr Yano, Nagoya City University Medical School, Department of Surgery II, 1 Kawasumi, Mizuho, Nagoya, Aichi 467–8601, Japan (Email: motoki{at}med.nagoya-cu.ac.jp).
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Abstract
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Thymic carcinoids are classified into three categories: (1) nonsecretory tumors, (2) hormonal secretory tumors, and (3) tumors associated with multiple endocrine neoplasia type 1. We report a rare case with adrenocorticotropic hormone secreting thymic carcinoid with multiple endocrine neoplasia type 1. Radiologic examination showed an anterior mediastinal mass and a parathyroid tumor. Blood analysis revealed high levels of parathyroid hormone and adrenocorticotropic hormone. Urine cortisol and 17-hydroxycorticoids levels were also elevated. Extended thymectomy was performed. Subsequently adjuvant radiation therapy and parathyroid tumor resection were performed. A germline mutation of exon 7 in the multiple endocrine neoplasia type 1 gene was detected and a somatic mutation of exon 9 was demonstrated in the thymic tumor.
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Introduction
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Neuroendocrine carcinomas (carcinoid) of the thymus are unusual neoplasms that account for 2% to 4% of all mediastinal tumors. Rosai and Higa [1] were the first to describe the primary neuroendocrine tumors in the thymus in 1972 and it was subsequently found to be associated with multiple endocrine neoplasia type 1 (MEN1) [2]. Multiple endocrine neoplasia type 1 related thymic carcinoids constitute approximately 10% to 25% of all cases of thymic carcinoids [3]. Thymic carcinoids associated with Cushing's syndrome are more frequent and account for 29% to 38% of all thymic carcinoids [3]. However MEN1 and Cushing's syndrome have never been reported to be associated in a single patient. We report a rare case of adrenocorticotropic hormone (ACTH) secreting thymic carcinoid with MEN1.
A 61-year-old man had been treated for hypertension and diabetes for 2 years when an anterior mediastinal tumor was pointed out. Leg edema and moon face with flushing were also noticed at the time of admission. He did not have any other typical symptoms of Cushing's syndrome. A definite diagnosis of multiple endocrine neoplasia type 1 (MEN1) is lacking, but one of his daughters was diagnosed with pancreatic tumor, and another daughter had a thyroid tumor. Chest roentgenograms and computed tomographic scan demonstrated an anterior mediastinal mass (Fig 1A) greater than 15 cm in diameter, and an ultrasound-guided percutaneous biopsy revealed a carcinoid tumor of the thymus. He had no diarrhea or heart disease in carcinoid syndrome, but flushing was noticed. Preoperative blood analysis showed hypercalcemia (11.2 mg/dL: normal, 9.0 to 10.6 mg/dL) and hypokalemia (3.2 mEq/L, 3.6 to 4.9 mEq/L). Adrenocorticotropic hormone (120 pg/mL, 6 to 36 pg/mL), intact parathyroid hormone (213 pg/mL, 10 to 60 pg/mL), and carcinoembryonic antigen (8.8 ng/mL, 5 ng/mL) were elevated. Urine cortisol (1,560 µg/d, 11 to 80 µg/d) and 17-hydroxycorticoids (17-OHCS) (32.7 mg/L, 3.4 to 12 mg/L) were also elevated. On chest computed tomography an anterior mediastinal mass, an anterior mediastinal lymph node swelling, and retrosternal neovascularization were pointed out (Fig 1B). Parathyroid subtraction scintigrams and cervical computed tomography showed a parathyroid tumor. These tumors were suspected to be responsible for hypercalcemia and a high level of intact parathyroid hormone. Brain magnetic resonance imaging was performed, and it did not show any abnormalities in the pituitary gland. Under a diagnosis of thymic carcinoid with Cushing's syndrome, tumor resection was performed through a median sternotomy. The neovascularization around the tumor was prominent and caused massive blood loss (5,180 mL) during the operation. The tumor was mostly encapsulated with locally invasive growth into the pleura. Extended thymectomy and partial resection of the invaded pleura were performed. Adjuvant radiation therapy to the mediastinum was performed (46 Gy). Postoperatively, hypertension was cured without any treatment. Diabetes persisted, but it has been well controlled without insulin injection. Urine cortisol (74 µg/d, 11 to 80 µg/d) was normalized within 1 month after surgery. Also the concentration of calcium (10.5 mg/dL), ACTH (30 pg/mL), and intact parathyroid hormone (60 pg/mL) were normalized. The pathologic examination of the tumor showed typical findings of thymic carcinoid with a single lymph node metastasis in the anterior mediastinum. Oval or round tumor cells with eosinophilic cytoplasm and uniformly oval nuclei are arranged as a ribbon-like growth pattern with rosette formations. In immunohistochemistry, chromogranin and synaptophysin, neuroendocrine markers were stained positively. Furthermore, diffuse and gross positive signals in the cytoplasm for ACTH were observed on immunohistochemistry (Fig 2). The serum calcium and intact parathyroid hormone, which had been normalized postoperatively, gradually increased. The following operation, parathyroid tumor resection, was performed 8 months after the primary operation. The pathological findings of the resected specimen demonstrated hyperplasia. Twenty-three months after the primary operation, multiple abdominal lymph node swellings, pleural dissemination, and effusion appeared and was diagnosed as a recurrence. The patient received a somatostatin analogue regimen (ie, octreotide acetate). Pleural effusion disappeared soon. This treatment seemed to be effective for him and the disease is still present but stable. He is alive with disease 31 months after the first operation.
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Fig 1. A large tumor at the anterior mediastinum as demonstrated (A) on chest roentgenogram and (B) on computed tomographic scan.
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Fig 2. Adrenocorticotropic hormone immunohistochemical staining. Diffuse positive signals in the cytoplasm were observed.
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After informed consent was obtained, a blood sample was drawn. Multiple endocrine neoplasia type 1 gene mutation analysis was performed from blood and tumor samples by direct nucleotide sequencing. Polymerase chain reaction and direct sequencing of exons 2 to 10 of MEN1 gene were performed. The DNA of the blood sample showed 1 base pair deletion of exon 7, codon 311 (ACC
AC). In addition, the thymic tumor DNA showed 2 base pairs deletion of exon 9, codon 440 (CTTT). The tumors and blood samples of the patient's daughters were not studied for MEN1 mutations.
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Comment
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Multiple endocrine neoplasia type 1 is an autosomal dominant familial cancer syndrome with a spectrum of tumors of the parathyroids, gastroenteropancreatic endocrine tissues, and the anterior pituitary. Other less common associations include a carcinoid tumor of the thymus. In retrospective studies, thymic carcinoids occurred at a rate of 3% to 4.9% in the patients with MEN1. In a recent prospective study, 8% of patients with MEN1 had a thymic carcinoid tumor develop during the observation period [4]. The gene responsible for MEN1 was mapped to chromosome 11q13 by linkage analysis and by studies on loss of heterozygosity (LOH) in MEN1-related tumors [5]. The MEN1 gene contains 10 exons and encodes a 610-amino acid protein termed menin [6], the function of which is unclear. The MEN1 gene is a putative tumor suppressor gene. In patients with MEN1, a high prevalence of heterozygous germline MEN1 mutations was reported [6] [7]. About 100 different mutations have been identified in familial and sporadic MEN1 in the United States, Canada, Europe [7] and Japan. In our case, 1 base pair deletion in the exon 7, codon 311 (ACCAC) was detected. This deletion has not been reported elsewhere. Exon 7 is one of the hot spots of mutations, the highest frequency found in exons 2 and 3 [7]. We did not perform LOH analysis of the MEN1 locus in the present study. In a recent report, LOH at the MEN1 locus on 11q13 was not found in thymic carcinoids associated with MEN1, although it is common in the other MEN1 related neoplasms [4]. In the present case, the tumor DNA showed an additional 2 base pairs deletion of the exon 9, codon 440 (CTTT). If this deletion had occurred in the wild type allele causing the inactivation of the MEN1 gene, it may have played a role in the generation of the thymic carcinoid in this patient.
Wick and colleagues classified thymic carcinoids classically into three groups: (1) one involving tumors associated with Cushing's syndrome or other endocrinopathies; (2) another one involving tumors not associated with endocrine abnormalities; and (3) another one including tumors associated with MEN [3]. Thymic carcinoids associated with MEN1 rarely secret functional hormones. In the present study, before diagnosis of a mediastinal tumor, he had symptoms of hypertension and leg edema. Serum level of ACTH, and urine levels of cortisol and 17-OHCS were significantly elevated. Upon immunohistochemistry, ACTH secretion was observed. It is very rare that thymic carcinoid associated with MEN1 secrets ACTH.
Thymic carcinoids often behave aggressively. Invasion of adjacent mediastinal structures, local recurrence, or metastases are common. Moran and Suster [8] reported poor prognosis of 50 patients with primary neuroendocrine carcinomas of the thymus. Overall survival rate for these patients was 28% at 5 years and 10% at 10 years. This poor prognosis depends on the tumor grades. Prognosis of thymic carcinoids associated with Cushing's syndrome has been reported to be worse than its other thymic carcinoids [3]. Poor prognosis of the present patient was easily predicted. Recurrence appeared 23 months after the first operation, although the tumor grade was low (typical carcinoid). Fortunately the present patient is on a somatostatin analogue regimen, which apparently has been effective so far. Continuous treatment and close observation are necessary for him.
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References
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- Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic origin related to carcinoid tumorClinicopathological study of 8 cases. Cancer 1972:1061-1074.
- Rosai J, Higa E, Davie J. Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosisA previously unrecognized association. Cancer 1972:1075-1083.
- Wick MR, Scott RE, Li CY, Carney JA. Carcinoid tumor of the thymusA clinicopathologic report of seven cases with a review of the literature. Mayo Clin Proc 1980;55:246-254.[Medline]
- Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1 J Clin Endocrinol Metab 2003;88:1066-1081.[Abstract/Free Full Text]
- Bystrom C, Larsson C, Blomberg C, et al. Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors Proc Natl Acad Sci USA 1990;87:1968-1972.[Abstract/Free Full Text]
- Chandrasekharappa SC, Guru SC, Manickam P, et al. Positive cloning of the gene for multiple endocrine neoplasia-type 1 Science 1997;276:404-407.[Abstract/Free Full Text]
- Bassett JHD, Forbes SA, Pannett AAJ, et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1 Am J Hum Genet 1998;62:232-244.[Medline]
- Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymusA clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000;114:100-110.[Medline]
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Abstract
Introduction
