Mediastinal Mass in a 25-Year-Old Man

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1 [ Chest Imaging and Pathology for Clinicians ] Mediastinal Mass in a 25-Year-Old Man Abhijeet Waghray, MD ; Lakpa Sherpa, MD ; Gandhari Carpio, MD ; and Timothy J. Barreiro, DO, FCCP A 25-year-old black man presented with left-sided chest pain and cough for 3 days. His pain was pressure-like and nonradiating and was aggravated with movement and relieved when the patient lay at a 45 angle. The patient denied fevers, chills, night sweats, and swelling but reported gaining 4 to 6 kg (10 to 15 lbs) in the past few months. His cough had started 2 weeks prior with yellow mucus production but he denied facial swelling or tenderness. He had no chronic medical conditions and was not taking medications. He had no known exposure to chemicals, fumes, or dust and no history of tobacco or alcohol abuse. CHEST 2014; 146 ( 2 ): e47 - e51 On examination, vital signs were unremarkable, and physical examination results were normal, including no testicular lesions, lymphadenopathy, or thyromegaly. Chest sounds were clear to auscultation, with no cardiac murmurs. Abdominal examination revealed no hepatosplenomegaly or bruits. Pulses were equal with no skin anomalies. Chest radiograph revealed a left mediastinal mass ( Fig 1A ). Further evaluation by CT scan with IV contrast demonstrated a 1037 cm anterior mediastinal mass with heterogeneous appearance and 50 Hounsfield Unit ( Fig 1B ). Laboratory data revealed the following values: lactate dehydrogenase of 193 U/L (reference range, U/L), α-fetoprotein of 3 ng/ml (reference range, ng/ml), β-2 microglobulin of 1.5 mg/l (reference range, mg/l), thyroid-stimulating hormone of μiu/ml (reference range, μiu/ml), intact parathyroid hormone of 44 pg/ml (reference range, pg/ml), calcium of 10.1 mg/dl (reference range, mg/dl), luteinizing hormone of 8.4 miu/ml (reference range, miu/ml), and follicle-stimulating hormone of 2.4 miu/ml (reference range, miu/ml). Flow cytometry results for lymphoma and HIV were negative. Tissue pathology revealed tumor cells with uniform cellular pattern, with round nuclei, even chromatin, and trabecula. Seven mitotic figures per 10 high-powered fields (HPFs) were visualized with areas of necrosis (Fig 2 ). Figure 1 A, Left mediastinal mass on chest radiograph (posteroanterior view). B, CT scan measuring cm with mild heterogeneous appear ance and compression of the right ventricular outflow tract and proximal main pulmonary artery, with encasement of the left upper-lobe bronchus. Manuscript received June 22, 2013 ; revision accepted February 18, AFFILIATIONS: From the Department of Medicine (Dr Waghray), Case Western Reserve University MetroHealth Medical Center, Cleveland; St. Elizabeth Health Center (Drs Sherpa and Carpio), Youngstown; Ohio University Heritage College of Medicine (Drs Sherpa and Carpio), Athens; and Northeast Ohio Medical University (Dr Barreiro), Rootstown, OH. CORRESPONDENCE TO: Timothy J. Barreiro, DO, FCCP, 1044 Belmont Ave, Youngstown, OH 44505; tbarreiro@neomed.edu 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest e47

2 Figure 2 Tissue pathology. A, Well-circumscribed carcinoid tumor with area of necrosis (left) on low power (magnification 3 40). B, Well-circumscribed carcinoid tumor on high power with mitosis (arrows) (magnification 3 100). C, Carcinoid tumor with uniform cellular pattern with round nuclei, even chromatin, and trabecula (magnification 3 400). What is the diagnosis? e48 Chest Imaging and Pathology for Clinicians [ 146#2 CHEST AUGUST 2014 ]

3 Diagnosis: Thymic atypical carcinoid tumor Discussion The differential diagnosis for an anterior mediastinal mass includes lymphoma, germ-cell tumor, parathyroid tumor, pericardial cyst, thymic mass, metastatic disease, and thyroid tumor. Thymic masses represent a broad category that includes thymomas, carcinomas, cysts, lipomas, and neuroendocrine tumors (NETs). Specifically, thymic malignancies are relatively rare, accounting for 0.13 cases per 100,000 population, with the majority of cases classified as thymomas. 1 Thymomas should not be considered benign. Histopathologically, they are staged into four groups; stage I thymomas represent noninvasive tumors with an intact capsule, whereas stage III and IV correspond to tissue invasion (blood vessels or lung tissue) and lymph node involvement/ distant metastasis, respectively. 2 They represent 47% of anterior mediastinal tumors with a peak incidence between 35 and 70 years of age and with nearly equal sex predilection. 2,3 A wide spectrum of diseases is associated with thymomas, including myasthenia gravis, which occurs in 30% to 50% of patients. 4 Further associated paraneoplastic syndromes include pure red aplasia, seen in 5% of patients, and hypogammaglobulinemia, seen in 10% of patients. 5 Grossly, early-stage thymomas appear as smooth round or oval masses but in advanced stages, calcifications and irregular margins will be present. NETs are the least common thymic malignancy, with presentation after the fifth decade of life and predominantly in men. 6 Since being first described in 1972 by Rosai and Higa, 7 approximately 150 cases of thymic NETs have been reported in the literature, with atypical pathologic characteristics representing a minority subset. Thymic NETs arise from the foregut and, unlike the more common midgut carcinoids, are more aggressive, locally invasive, larger in size, and not associated with carcinoid syndrome. Vague symptom presentation (cough, chest pain, and dyspnea) often cause patient delay in seeking medical care and results in 20% to 40% of patients with metastatic disease (chest wall, lung, liver, brain) at presentation, 6,8 whereas advanced disease presents with recurrent pulmonary infections, hemoptysis, hoarseness from laryngeal nerve involvement, Horner syndrome, and superior vena cava obstruction. 9,10 Increased medical imaging is now identifying mediastinal masses in asymptomatic patients and may affect prognosis. Of note, the patient experienced a weight gain of 4 to 6 kg, rather than losing weight as expected with malignancy. Approximately 20% of patients with thymic carcinoid tumors have Cushing syndrome. Although specific testing was not completed to document Cushing syndrome, in the current patient it would account for the weight gain. As with any mediastinal mass, laboratory tests should be used to narrow the diagnosis. Thyroid function and serum calcium, parathyroid hormone, and phosphate studies help determine thyroid and parathyroid tumors. Male patients, at risk of germ-cell tumors, should have α-fetoprotein, β-human chorionic gonadotropin, and β-2 microglobulin levels measured. Approximately 25% of patients with thymic NETs have associated multiple endocrine neoplasia type 1 (MEN 1). 11 Therefore, thymic carcinoid patients are often evaluated for malignancies associated with MEN 1 syndrome 11 by genetic sequence analysis of the MEN gene for mutations. Clinical Discussion Scientific data to guide therapy are limited to case reports or case series, but definitive surgery remains the mainstay of therapy. The aggressive nature of these tumors requires open surgical resection. Invasive tumors undergo debulking to provide symptomatic relief and facilitate adjuvant treatment. Medical modalities, including chemotherapy with streptozosin, etoposide, fluorouracil, or cisplatin, have been studied but have not provided survival benefit or reduction in recurrence rates. 12 Nonetheless, reports have suggested a postoperative irradiation response, especially in invasive carcinoid tumors. 13,14 Recently, case reports and small studies have evaluated genomic profiling as a means of targeting therapy in thymomas and thymic carcinomas. 15 Efforts to determine molecular differences to establish treatment are ongoing, but the paucity of thymic malignancies limits large-scale trials. Further, high rates of local recurrence are common even after complete surgical resection and contribute to an overall poor prognosis. Currently, no evidence-based guidelines exist for posttherapy surveillance, although follow-up imaging may be of benefit. Five-year survival with thymic NETs is around 50%, although survival data on atypical carcinoid tumors are again limited. 16 Radiologic Discussion Mediastinal masses are usually incidental findings on routine chest radiographs. Review of previous imaging is important with specific diligence for small overlooked masses. Mediastinal masses must also be differentiated from lung parenchyma masses. Unlike lung masses, e49

4 mediastinal masses have obtuse angles of interface, lack air bronchograms, and may interfere with mediastinal margins (ie, azygoesophogeal recess). Further, identification of fat, cyst spaces, or bone on CT scan may be crucial to differentiate fat-containing germ-cell tumors from nonfat/cystic lesions. A CT scan with IV contrast is needed to assess the location and morphology of mediastinal disease and to evaluate vascular proximity. Ideally, precontrast and postcontrast imaging should be obtained, which can discriminate cystic lesions from solid or necrotic lesions. NETs appear as large lobulated masses with a heterogenous appearance, and areas of local invasion, necrosis, or hemorrhage may be identified. No guidelines exist for when MRI should be used to evaluate a patient with thymic carcinoids, but this imaging modality, compared with CT scanning, may better differentiate cystic from solid lesions, and newer imaging modalities such as chemicalshift MRI may aid in distinguishing thymomas from nonneoplastic thymic lesions. 17 However, the usefulness of MRI should be weighed against added cost, and one should consider whether the findings will affect management compared with information from a CT scan alone. Somatostatin receptor scintigraphy is helpful in identifying these tumors and determining metastasis. 18 However, its usefulness depends on the expression of somatostatin receptors; a negative test does not eliminate the diagnosis of thymic carcinoid. 19 Thus, radiographic imaging alone is insufficient for a diagnosis of NETs. A biopsy is often required to exclude lymphoma and germ-cell tumors because medical treatment is preferred over resection in these cases. PET scans can evaluate for disease metastasis. Although they need further validation, PET scans maybe used in the future for the workup of anterior mediastinal masses to differentiate aggressive thymic malignancies (carcinoma, carcinoid) from thymomas, 20 with one study demonstrating a standardized uptake value cutoff of 5.0 having a sensitivity of 84.6%, a specificity of 92.3%, and an accuracy of 88.5%. 21 Pathologic Discussion Thymic NETs are classified as typical, atypical, or smallcell or large-cell carcinoid neoplasms according to the 2004 World Health Organization classification system, which is based on tumor necrosis, differentiation, and proliferative rate. The atypical subset represents the minority. Typical carcinoid neoplasms are well differentiated without necrosis and less than two mitotic figures per 10 HPFs. Atypical carcinoid tumors are also well differentiated but have two to 10 mitotic figures per HPFs with necrosis. Poorly differentiated tumors with. 10 mitotic figures per HPFs are classified as small- or large-cell carcinoid neoplasms based on cytology. 22 It should be noted that this classification is adapted from pulmonary NETs, and the prognostic value of using these criteria has not been established in thymic NETs. Immunohistochemical stains are used to confirm the diagnosis of NETs. Positive reactions were observed using antibodies for low-molecular-weight cytokeratins, broad-spectrum keratin, chromogranin, synaptophysin, and Leu-7, although the laboratory availability of markers varies. Given the subtle characteristics of anterior mediastinal NETs, multidisciplinary confirmation of tumors is necessary. Grossly, thymic NETs are encapsulated neoplasms with gray-tan colored surface and areas of hemorrhage and necrosis. 7 Histologic features include trabecula, organoid nests, or rosettes forming a uniform cellular pattern ( Fig 2 ). Cellular release of neurosecretory granules is reflected by elevated serum chromogranin and synaptophysin levels. Conclusions Testing in this patient was negative for MEN 1 syndrome, including normetanephrine level of 0.50 nmol/l (reference range, nmol/l), free metanephrine level of 0.24 nmol/l (reference range, nmol/l), and normal intact parathyroid hormone and calcium levels. Staging was completed via head CT scans and PET scans, which were negative for metastatic disease. CT image-guided core needle biopsy in this patient showed granular structures consistent with NETs and, importantly, excluded lymphoma and germ cell tumor. He underwent complete resection of the tumor with complex dissection off the innominate vein and preservation of the left phrenic nerve with lymph node sampling. Tissue pathology revealed a grade II atypical carcinoid thymic tumor with seven mitotic figures per 10 HPFs and geographic areas of necrosis. The postoperative course was uncomplicated, and the patient was discharged home within 2 days. Diagnostic follow-up for recurrence will include chest CT scans every 4 months with serologic evaluation of chromogranin and 5-hydroxyindoleacetic levels. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met. e50 Chest Imaging and Pathology for Clinicians [ 146#2 CHEST AUGUST 2014 ]

5 References 1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol ;5 (10 )(suppl 4 ):S260-S Q u YJ, L iu GB, Shi HS, L i ao MY, Yang GF, Ti an ZX. Pre operative CT findings of thymoma are correlated with postoperative Masaoka clinical stage. Acad Radiol ;20(1): Detterbeck FC. Evaluation and treatment of stage I and II thymoma. J Thorac Oncol ;5(10)(suppl 4 ):S318-S Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med ;38 (6 ): Tormoehlen LM, Pascuzzi RM. Thymoma, myasthenia gravis, and other paraneoplastic syndromes. Hematol Oncol Clin North Am ;22 (3 ): Chaer R, Massad MG, Evans A, Snow NJ, Geha AS. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg ;74 (5 ): Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer ;29(4): Ti ffe t O, Ni chols on AG, L ad as G, Shepp ard MN, G ol dst raw P. A clinicopathologic study of 12 neuroendocrine tumors arising in the thymus. Chest ;124(1): de Montpréville VT, Macchiarini P, Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg ;111(1): Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol ;114(1): Teh BT, McArdle J, Chan SP, et al. Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1. Medicine (Baltimore) ;76(1): Takahashi T, Hatao K, Yamashita Y, Tanizawa Y. Ectopic ACTH syndrome due to thymic atypical carcinoid treated with combination chemotherapy of cisplatin and etoposide. Intern Med ;42(12): Filosso PL, Actis Dato GM, Ruffini E, Bretti S, Ozzello F, Mancuso M. Multidisciplinary treatment of advanced thymic neuroendocrine carcinoma (carcinoid): report of a successful case and review of the literature. J Thorac Cardiovasc Surg ;127(4): Economopoulos GC, Lewis JW Jr, Lee MW, Silverman NA. Carcinoid tumors of the thymus. Ann Thorac Surg ;50(1): Kelly RJ. Thymoma versus thymic carcinoma: differences in biology impacting treatment. J Natl Compr Canc Netw ; 11 ( 5 ): Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Ann Surg ;251(6): Juanpere S, Cañete N, Ortuño P, Martínez S, Sanchez G, Bernado L. A diagnostic approach to the mediastinal masses. Insights Imaging ;4(1): Guidoccio F, Grosso M, Maccauro M, et al. Current role of 111 In-DTPA-octreotide scintigraphy in diagnosis of thymic masses. Tumori ;97(2): 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 ;88 (3 ): Benveniste MF, Moran CA, Mawlawi O, et al. FDG PET-CT aids in the preoperative assessment of patients with newly diagnosed thymic epithelial malignancies. J Thorac Oncol ; 8 ( 4 ): Sasaki M, Kuwabara Y, Ichiya Y, et al. Differential diagnosis of thymic tumors using a combination of 11 C-methionine PET and FDG PET. J Nucl Med ;40(10): Rindi G. A.R., Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman TF, C ar ne iro F, Hr ub an RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France : International Agency for Research on Cancer (IARC); e51

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