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English Pages 276 Year 2021
Song Zhang Editor
Diagnostic Imaging of Mediastinal Diseases
Diagnostic Imaging of Mediastinal Diseases
Song Zhang Editor
Diagnostic Imaging of Mediastinal Diseases
Editor Song Zhang Department of Respiratory and Critical Care Medicine Shandong Provincial Hospital Affiliated to Shandong First Medical University Shandong China
ISBN 978-981-15-9929-3 ISBN 978-981-15-9930-9 (eBook) https://doi.org/10.1007/978-981-15-9930-9 Jointly published with Science Press © Science Press 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore
Original Intention
One more time, I am wandering in the avenue of the hospital. With a leisurely moat, Flowing quietly. Slantly when the afterglow , Pouring on the mottled bank, I walk through the familiar corridor back and forth. As same as the Wisteria, which looks like the clouds and waterfalls, Blossom to withers, again and again. The layer and layer of high buildings are standing quietly. Right here, How many times, I welcome these Angel’s arrival, How many times, I sadly farewell to those tired soul. Passing by the library, Going through the teaching building, Those young faces are glinting in the dusk. Years ago, I also own such a beautiful youth. In the shade of the cherry trees, gorgeously as the sunset, The evening breeze blows gently. Please fall a petal rain for me. Even when the beauty face aging, the black hair growing gray, But my soft heart, Is still pure as before.
Pudong New Area, Shanghai, China
Huang Chen
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Contents
1 Thymic Hyperplasia��������������������������������������������������������������������������������������������������� 1 Dan Cheng and Song Zhang 1.1 Thymic Development and Anatomy ������������������������������������������������������������������� 1 1.2 Classification������������������������������������������������������������������������������������������������������� 1 1.3 Clinical Features ������������������������������������������������������������������������������������������������� 3 1.4 Radiographic Features����������������������������������������������������������������������������������������� 3 1.5 Differential Diagnosis ����������������������������������������������������������������������������������������� 4 1.6 Treatment������������������������������������������������������������������������������������������������������������� 5 1.7 Case Analysis������������������������������������������������������������������������������������������������������� 5 1.7.1 Case 1������������������������������������������������������������������������������������������������������� 5 1.7.2 Case 2������������������������������������������������������������������������������������������������������� 7 References��������������������������������������������������������������������������������������������������������������������� 8 2 Thymic Cyst����������������������������������������������������������������������������������������������������������������� 9 Dan Cheng and Song Zhang 2.1 Classification������������������������������������������������������������������������������������������������������� 9 2.2 Clinical Features ������������������������������������������������������������������������������������������������� 9 2.3 Histopathology����������������������������������������������������������������������������������������������������� 9 2.4 Radiographic Features����������������������������������������������������������������������������������������� 9 2.5 Differential Diagnosis ����������������������������������������������������������������������������������������� 12 2.6 Treatment������������������������������������������������������������������������������������������������������������� 12 2.7 Case Analysis������������������������������������������������������������������������������������������������������� 13 2.7.1 Case 1������������������������������������������������������������������������������������������������������� 13 2.7.2 Case 2������������������������������������������������������������������������������������������������������� 15 References��������������������������������������������������������������������������������������������������������������������� 17 3 Thymic Epithelial Tumor������������������������������������������������������������������������������������������� 19 Cheng-sen Cai and Song Zhang 3.1 Epidemiology������������������������������������������������������������������������������������������������������� 19 3.2 Classification������������������������������������������������������������������������������������������������������� 19 3.3 Clinical Features ������������������������������������������������������������������������������������������������� 22 3.4 Radiographic Features����������������������������������������������������������������������������������������� 22 3.5 Differential Diagnosis ����������������������������������������������������������������������������������������� 25 3.6 Treatment������������������������������������������������������������������������������������������������������������� 27 3.7 Recurrence����������������������������������������������������������������������������������������������������������� 28 3.8 Case Analysis������������������������������������������������������������������������������������������������������� 28 3.8.1 Case 1������������������������������������������������������������������������������������������������������� 28 3.8.2 Case 2������������������������������������������������������������������������������������������������������� 31 3.8.3 Case 3������������������������������������������������������������������������������������������������������� 32 3.8.4 Case 4������������������������������������������������������������������������������������������������������� 36 3.8.5 Case 5������������������������������������������������������������������������������������������������������� 38 3.8.6 Case 6������������������������������������������������������������������������������������������������������� 40 3.8.7 Case 7������������������������������������������������������������������������������������������������������� 43 vii
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3.8.8 Case 8������������������������������������������������������������������������������������������������������� 45 3.8.9 Case 9������������������������������������������������������������������������������������������������������� 46 3.8.10 Case 10����������������������������������������������������������������������������������������������������� 49 3.8.11 Case 11����������������������������������������������������������������������������������������������������� 50 3.8.12 Case 12����������������������������������������������������������������������������������������������������� 52 3.8.13 Case 13����������������������������������������������������������������������������������������������������� 52 3.8.14 Case 14����������������������������������������������������������������������������������������������������� 54 3.8.15 Case 15����������������������������������������������������������������������������������������������������� 57 3.8.16 Case 16����������������������������������������������������������������������������������������������������� 58 3.8.17 Case 17����������������������������������������������������������������������������������������������������� 60 References��������������������������������������������������������������������������������������������������������������������� 64 4 Neuroendocrine Tumors of the Thymus������������������������������������������������������������������� 65 Yao Shen and Song Zhang 4.1 Classification������������������������������������������������������������������������������������������������������� 65 4.2 Pathology������������������������������������������������������������������������������������������������������������� 65 4.3 Clinical Features ������������������������������������������������������������������������������������������������� 66 4.4 Radiographic Features����������������������������������������������������������������������������������������� 66 4.5 Treatment������������������������������������������������������������������������������������������������������������� 67 4.6 Prognosis������������������������������������������������������������������������������������������������������������� 69 4.7 Case Analysis������������������������������������������������������������������������������������������������������� 69 4.7.1 Case 1������������������������������������������������������������������������������������������������������� 69 4.7.2 Case 2������������������������������������������������������������������������������������������������������� 71 4.7.3 Case 3������������������������������������������������������������������������������������������������������� 73 4.7.4 Case 4������������������������������������������������������������������������������������������������������� 74 4.7.5 Case 5������������������������������������������������������������������������������������������������������� 76 4.7.6 Case 6������������������������������������������������������������������������������������������������������� 77 References��������������������������������������������������������������������������������������������������������������������� 79 5 Mediastinal Lymphoma��������������������������������������������������������������������������������������������� 81 Li Xu and Song Zhang 5.1 Classification������������������������������������������������������������������������������������������������������� 81 5.2 Clinical Features ������������������������������������������������������������������������������������������������� 81 5.3 Radiographic Features����������������������������������������������������������������������������������������� 81 5.4 Treatment������������������������������������������������������������������������������������������������������������� 86 5.5 Case Analysis������������������������������������������������������������������������������������������������������� 86 5.5.1 Case 1������������������������������������������������������������������������������������������������������� 86 5.5.2 Case 2������������������������������������������������������������������������������������������������������� 88 5.5.3 Case 3������������������������������������������������������������������������������������������������������� 90 5.5.4 Case 4������������������������������������������������������������������������������������������������������� 92 5.5.5 Case 5������������������������������������������������������������������������������������������������������� 93 5.5.6 Case 6������������������������������������������������������������������������������������������������������� 95 5.5.7 Case 7������������������������������������������������������������������������������������������������������� 99 5.5.8 Case 8������������������������������������������������������������������������������������������������������� 102 References��������������������������������������������������������������������������������������������������������������������� 104 6 Mediastinal Granulocytic Sarcoma��������������������������������������������������������������������������� 105 Dan Cheng and Song Zhang 6.1 Classification������������������������������������������������������������������������������������������������������� 105 6.2 Pathogenesis��������������������������������������������������������������������������������������������������������� 105 6.3 Clinical Features ������������������������������������������������������������������������������������������������� 106 6.4 Diagnosis������������������������������������������������������������������������������������������������������������� 106 6.5 Treatment������������������������������������������������������������������������������������������������������������� 106 6.6 Prognosis������������������������������������������������������������������������������������������������������������� 107
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6.7 Case Analysis������������������������������������������������������������������������������������������������������� 107 6.7.1 Case 1������������������������������������������������������������������������������������������������������� 107 6.7.2 Case 2������������������������������������������������������������������������������������������������������� 109 References��������������������������������������������������������������������������������������������������������������������� 110 7 Mediastinal Germ Cell Tumor����������������������������������������������������������������������������������� 111 Hong-Mei Wang and Song Zhang 7.1 Pathogenesis��������������������������������������������������������������������������������������������������������� 111 7.2 Genetics��������������������������������������������������������������������������������������������������������������� 112 7.3 Pathology������������������������������������������������������������������������������������������������������������� 112 7.4 Immunohistochemistry ��������������������������������������������������������������������������������������� 113 7.5 Clinical Features ������������������������������������������������������������������������������������������������� 113 7.6 Radiographic Features����������������������������������������������������������������������������������������� 114 7.7 Serum Markers����������������������������������������������������������������������������������������������������� 114 7.8 Treatment������������������������������������������������������������������������������������������������������������� 114 7.9 Prognosis������������������������������������������������������������������������������������������������������������� 114 7.10 I Teratoma ����������������������������������������������������������������������������������������������������������� 115 7.11 Case Analysis������������������������������������������������������������������������������������������������������� 118 7.11.1 Case 1������������������������������������������������������������������������������������������������������� 118 7.11.2 Case 2������������������������������������������������������������������������������������������������������� 118 7.11.3 Case 3������������������������������������������������������������������������������������������������������� 121 7.11.4 Case 4������������������������������������������������������������������������������������������������������� 123 7.11.5 Case 5������������������������������������������������������������������������������������������������������� 125 7.11.6 Case 6������������������������������������������������������������������������������������������������������� 127 7.11.7 Case 7������������������������������������������������������������������������������������������������������� 130 7.11.8 Case 8������������������������������������������������������������������������������������������������������� 131 7.11.9 Case 9������������������������������������������������������������������������������������������������������� 133 7.12 II Seminoma��������������������������������������������������������������������������������������������������������� 135 7.13 Etiology��������������������������������������������������������������������������������������������������������������� 135 7.14 Epidemiology������������������������������������������������������������������������������������������������������� 135 7.15 Clinical Features ������������������������������������������������������������������������������������������������� 136 7.16 Radiographic Features����������������������������������������������������������������������������������������� 136 7.17 Diagnosis������������������������������������������������������������������������������������������������������������� 137 7.18 Treatment������������������������������������������������������������������������������������������������������������� 138 7.19 Prognosis������������������������������������������������������������������������������������������������������������� 140 7.20 Case Analysis������������������������������������������������������������������������������������������������������� 140 7.20.1 Case 1������������������������������������������������������������������������������������������������������� 140 7.20.2 Case 2������������������������������������������������������������������������������������������������������� 142 7.20.3 Case 3������������������������������������������������������������������������������������������������������� 144 7.21 III Yolk Sac Tumor����������������������������������������������������������������������������������������������� 146 7.22 Epidemiology������������������������������������������������������������������������������������������������������� 146 7.23 Clinical Manifestations ��������������������������������������������������������������������������������������� 146 7.24 Radiographic Features����������������������������������������������������������������������������������������� 146 7.25 Histopathology����������������������������������������������������������������������������������������������������� 147 7.26 Diagnosis������������������������������������������������������������������������������������������������������������� 152 7.27 Treatment and Prognosis������������������������������������������������������������������������������������� 153 7.28 Case Analysis������������������������������������������������������������������������������������������������������� 153 7.28.1 Case 1������������������������������������������������������������������������������������������������������� 153 7.28.2 Case 2������������������������������������������������������������������������������������������������������� 155 7.29 IV Embryonal Carcinoma ����������������������������������������������������������������������������������� 158 7.30 Epidemiology������������������������������������������������������������������������������������������������������� 158 7.31 Clinical Features ������������������������������������������������������������������������������������������������� 158 7.32 Pathology and Immunohistochemistry ��������������������������������������������������������������� 158
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7.33 Differential Diagnosis ����������������������������������������������������������������������������������������� 159 7.34 Case Analysis������������������������������������������������������������������������������������������������������� 159 7.35 V Choriocarcinoma��������������������������������������������������������������������������������������������� 160 7.36 Epidemiology������������������������������������������������������������������������������������������������������� 160 7.37 Clinical Features ������������������������������������������������������������������������������������������������� 160 7.38 Radiographic Features����������������������������������������������������������������������������������������� 161 7.39 Pathology������������������������������������������������������������������������������������������������������������� 161 7.40 Treatment������������������������������������������������������������������������������������������������������������� 161 7.41 Prognosis������������������������������������������������������������������������������������������������������������� 161 7.42 Case Analysis������������������������������������������������������������������������������������������������������� 161 References��������������������������������������������������������������������������������������������������������������������� 165 8 Mediastinal Soft Tissue Tumor ��������������������������������������������������������������������������������� 167 Li Xu and Song Zhang 8.1 Case Analysis������������������������������������������������������������������������������������������������������� 167 8.1.1 Case 1������������������������������������������������������������������������������������������������������� 167 8.1.2 Case 2������������������������������������������������������������������������������������������������������� 168 8.1.3 Case 3������������������������������������������������������������������������������������������������������� 172 8.1.4 Case 4������������������������������������������������������������������������������������������������������� 174 8.1.5 Case 5������������������������������������������������������������������������������������������������������� 178 8.1.6 Case 6������������������������������������������������������������������������������������������������������� 180 8.1.7 Case 7������������������������������������������������������������������������������������������������������� 182 8.1.8 Case 8������������������������������������������������������������������������������������������������������� 185 8.1.9 Case 9������������������������������������������������������������������������������������������������������� 188 8.1.10 Case 10����������������������������������������������������������������������������������������������������� 189 8.1.11 Case 11����������������������������������������������������������������������������������������������������� 191 8.1.12 Case 12����������������������������������������������������������������������������������������������������� 192 8.1.13 Case 13����������������������������������������������������������������������������������������������������� 194 8.1.14 Case 14����������������������������������������������������������������������������������������������������� 196 8.1.15 Case 15����������������������������������������������������������������������������������������������������� 197 8.1.16 Case 16����������������������������������������������������������������������������������������������������� 199 8.1.17 Case 17����������������������������������������������������������������������������������������������������� 201 8.1.18 Case 18����������������������������������������������������������������������������������������������������� 203 9 Neurogenic Tumors����������������������������������������������������������������������������������������������������� 205 Jin Han and Song Zhang 9.1 Origin and Classification������������������������������������������������������������������������������������� 205 9.2 Schwannoma ������������������������������������������������������������������������������������������������������� 205 9.3 Neurofibroma������������������������������������������������������������������������������������������������������� 209 9.4 Ganglioneuroma��������������������������������������������������������������������������������������������������� 210 9.5 Neuroblastoma����������������������������������������������������������������������������������������������������� 213 9.6 Paraganglioma����������������������������������������������������������������������������������������������������� 220 9.7 Case Analysis������������������������������������������������������������������������������������������������������� 222 9.7.1 Case 1������������������������������������������������������������������������������������������������������� 222 9.7.2 Case 2������������������������������������������������������������������������������������������������������� 224 9.7.3 Case 3������������������������������������������������������������������������������������������������������� 225 9.7.4 Case 4������������������������������������������������������������������������������������������������������� 228 9.7.5 Case 5������������������������������������������������������������������������������������������������������� 229 9.7.6 Case 6������������������������������������������������������������������������������������������������������� 230 9.7.7 Case 7������������������������������������������������������������������������������������������������������� 233 9.7.8 Case 8������������������������������������������������������������������������������������������������������� 234 9.7.9 Case 9������������������������������������������������������������������������������������������������������� 238 9.7.10 Case 10����������������������������������������������������������������������������������������������������� 241 9.7.11 Case 11����������������������������������������������������������������������������������������������������� 242
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9.7.12 Case 12����������������������������������������������������������������������������������������������������� 244 9.7.13 Case 13����������������������������������������������������������������������������������������������������� 247 9.7.14 Case 14����������������������������������������������������������������������������������������������������� 248 9.7.15 Case 15����������������������������������������������������������������������������������������������������� 249 9.7.16 Case 16����������������������������������������������������������������������������������������������������� 251 9.7.17 Case 17����������������������������������������������������������������������������������������������������� 254 9.7.18 Case 18����������������������������������������������������������������������������������������������������� 257 9.7.19 Case 19����������������������������������������������������������������������������������������������������� 259 9.7.20 Case 20����������������������������������������������������������������������������������������������������� 261 9.7.21 Case 21����������������������������������������������������������������������������������������������������� 261 9.7.22 Case 22����������������������������������������������������������������������������������������������������� 264 9.7.23 Case 23����������������������������������������������������������������������������������������������������� 265 9.7.24 Case 24����������������������������������������������������������������������������������������������������� 266 References��������������������������������������������������������������������������������������������������������������������� 268
Editors and Contributors
Editor
Song Zhang Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China
Deputy-Editor Hong-Mei Wang Department of Gynecology and Obstetrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China Li Xu Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China
Co-Editors Dan Cheng Department of Respiration, Central Hospital of Haining, Zhejiang Province People’s Hospital Haining Hospital, Haining, China Jin Han Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai, China Yao Shen Department of Respiratory Medicine, Pudong Hospital Affiliated to Fudan University, Shanghai, China Cheng-Sen Cai Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Thymic Hyperplasia Dan Cheng and Song Zhang
Descriptions of the thymus date back to more than 2000 years ago, yet its functions were not known for centuries. The word thymus comes from the Latin derivation of the Greek word thymos, meaning warty excrescence due to its likeness to a bunch of thyme. Because thymos also means “soul” or “spirit,” the thymus was misrepresented as the seat of the soul by the ancient Greeks. Galen of Pergamum (129–200 AD), an ancient Greek physician, who first noted that the thymus was proportionally largest during infancy, referred to the thymus as an “organ of mystery,” a moniker that remained fairly accurate for almost two millennia.
1.1
Thymic Development and Anatomy
The thymus is a gland situated in the anterior mediastinum, embryologically derived from the third and fourth pairs of pharyngeal pouches. Over the next few weeks, this tissue migrates caudally and medially along the thymopharyngeal duct (deep to sternocleidomastoid muscle) to the anterior mediastinum. Subsequently, lymphoid cells from the liver and bone marrow migrate to the thymus, after that the thymus differentiates into a cortex and medulla. It overlies the pericardium, aortic arch, left innominate vein, and trachea. The thymus may extend superiorly to the lower pole of the thyroid and inferiorly to the diaphragm, which is attached to the thyroid by the thyrothymic ligament. Thymic lesions or ectopic thymic tissue can occur anywhere along the thymopharyngeal duct. The thymus is a lymphatic organ that plays an important role in the development and maturation of the immune system during childhood, specifically T cells, which are vital in D. Cheng Department of Respiration, Central Hospital of Haining, Zhejiang Province People’s Hospital Haining Hospital, Haining, China S. Zhang (*) Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China
regulating cellular immunity, and B cells, which are vital in regulating humoral immunity. The size of the thymus varies with age. From a birth mean weight of 15 g, the size grows until puberty to a mean weight of 30–40 g, and then, it undergoes progressive atrophy, to no more than 5–15 g in the elderly. In early infancy, it reaches its largest relative size, because its rate of increase is less than the rest of the body in a growing child. After the age of 2 years, the thymus is less frequently visible. As children grow older and their immune systems mature, the thymus undergoes physiologic involution, eventually leading to scattered lymphocytes present within adipose tissue, yet it maintains its original configuration. The normal thymus attenuation is significantly higher and easier to show a fuller quadrilateral shape in 20–30-year- old women than in men of the same age. On histologic examination, the thymus is organized into multiple lobules that are arranged into an outer cortex and an inner medulla. The cortex is composed of immature T-lymphocytes and thymic epithelial cells; the medulla is composed of maturing lymphocytes and whorls of spindle- shaped epithelial cells, which create Hassall corpuscles with keratinized cores.
1.2
Classification
Thymic hyperplasia consists of two subtypes, true hyperplasia and lymphoid hyperplasia (also known as follicular hyperplasia or lymphofollicular hyperplasia), which are clearly distinguished by pathologic analysis. These two entities are indistinguishable from one another at imaging. True thymic hyperplasia shows an enlarged thymus gland with an increase in normal thymus tissue, determined by weight and volume, beyond the upper limit of normal for which particular age. Although a hyperplastic thymus may retain its normal shape, it more commonly loses its unique bilobed appearance and instead appears oval. Clinically, true thymic hyperplasia can be divided into three groups: those without a related preexisting condition; those recovering
© Science Press 2021 S. Zhang (ed.), Diagnostic Imaging of Mediastinal Diseases, https://doi.org/10.1007/978-981-15-9930-9_1
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Fig. 1.1 A 20-year-old man had a history of hyperthyroidism and thymic hyperplasia, and complained of fear of heat and sweating for more than 2 months. Chest CT showed a triangular-shaped thymus with
arrowhead morphology, homogeneous soft-tissue attenuation similar to that of muscle and unenhanced vessels, and slightly concave borders
from a recent stress event such as pneumonia, corticosteroid therapy, radiation therapy, chemotherapy, surgery, or burns; and those with other disorders such as hyperthyroidism (Fig. 1.1), sarcoidosis, or red blood cell aplasia. In response to these stressors, the thymus first shrinks and then grows back when the stress is eliminated; the thymus sometimes continues to grow and become larger than its original size, which is referred to as “rebound hyperplasia.” Among patients with chemotherapy, approximately 10–25% may develop rebound hyperplasia, which usually occurs within 2 years of initiation of chemotherapy. However, there is a reported case of rebound hyperplasia that occurred 5 years after completion of chemotherapy. True thymic hyperplasia has been reported in a patient who received antitumor necrosis factor therapy for the treatment of rheumatic disease, in patients treated for human immunodeficiency virus infection, and in a patient following a severe infection. Additionally, Graves’ disease has attracted attention as a cause of true thymic hyperplasia. The mechanism through which Graves’ disease leads to true thymic hyperplasia has not yet been elucidated. So far, two possible mechanisms have been proposed. The first mechanism involves the expression of the TSH receptors in the thymus, which medi-
ates thymic overgrowth through an autoimmune response. In some thymic hyperplasia cases accompanied by Graves’ disease, the presence of TSH receptors in thymic tissues was revealed by a reverse transcription-polymerase chain reaction, northern blot analysis, and immunohistochemistry. Another mechanism involves the induction of hyperplasia in the thymus by the thyroid hormones. Nuclear T3 receptors are expressed in the murine thymic epithelium, and the thymus enlargement during T3 treatment. In addition, patients with Graves’ disease who underwent radioiodine treatment showed a reduction in thymic volume in parallel with a decrease in serum T3 levels. In lymphoid hyperplasia, the thymus gland is not always enlarged, can be atrophic, or can be involved with a neoplasm. Lymphoid hyperplasia, on the other hand, is characterized by the presence of an increased number of lymphoid follicles and germinal centers in the thymus. Unlike true hyperplasia, thymic lymphoid hyperplasia may occur with or without thymic enlargement. It is commonly associated with autoimmune diseases such as myasthenia gravis, thyrotoxicosis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and other autoimmune conditions and has been reported to occur in the early stages of human
1 Thymic Hyperplasia
i mmunodeficiency virus infection. Thymectomy is often performed in patients with myasthenia gravis because of the improvement of myasthenic symptoms after thymectomy. The pathogenesis of thymic hyperplasia remains unclear. In 1978, Levine et al. divided the thymic hyperplasia into two subtypes according to the characteristics of histomorphology [8]. The first is lymphoid follicular hyperplasia characterized by the presence of active lymphoid follicle primordial center. The pathophysiologic changes were as follows: thymic medulla expansion, cortex damage, and the presence as a chronic inflammatory reaction. The other is true thymic hyperplasia. The morphology and microstructure of true thymic hyperplasia were consistent with that of normal thymus in children’s age, but its volume and weight were significantly larger than that of normal thymus (Fig. 1.2). But this type of hyperplasia has never been found in any other tissues and organs. Lymphoid follicular hyperplasia is also known as autoimmune thymitis, which is usually self-limited and without the increase of thymus volume. Studies have shown that myasthenia gravis was closely related to lymphoid follicular hyperplasia but not related to the true thymic hyperplasia.
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1.3
Clinical Features
Thymic hyperplasia occurs in children or adolescents, which may be related to the active function of their thymus. Some patients may have congenital thymic hyperplasia, which were found in childhood due to symptoms or physical examinations. There was no significant difference between men and women. Hyperplastic thymus may oppress the trachea, bronchus, lung tissue, and heart. The patients usually have symptoms of respiratory and circulatory systems, such as cough, dyspnea, fatigue after activity, or recurrent respiratory infection.
1.4
Radiographic Features
Typically, the thymus is visible on a computed tomography (CT) scan and fills the perivascular space throughout the first 20 years of life. It typically appears quadrilateral with convex borders in children younger than 5 years. As children grow, the thymus gradually becomes triangular with straight
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Fig. 1.2 A 33-year-old woman complained of limb weakness in the afternoon for more than 3 months. Pathology showed the thymus tissue, the lobular structure retained the skin and medulla differentiation, and the normal distribution of lymphocytes and epithelial cells
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Fig. 1.3 Chest CT image in a 29-year-old woman showed a diffuse asymmetric enlarged thymus anterior to the aortic arch that exhibited lower attenuation compared to muscle and unenhanced vessels suggesting fatty infiltration
or concave borders. The left lobe is often slightly more prominent than the right, with concave or flat margins in the normal adult. On T1-weighted MR images (T1WI), adult thymic signal intensity is generally slightly greater than muscle but less than fat, and on T2-weighted images (T2WI) it is somewhat higher than muscle and equal to or slightly less than fat. The CT scan of thymic hyperplasia can have the following typical features: (1) the thymus in the anterior mediastinum is enlarged, especially the thickness is increased, but it still maintains its normal shape, which is round, trapezoid, rectangle, or pear shape (Fig. 1.3), with smooth edge and lobulated shape; (2) about 30–50% of thymic hyperplasia has normal size and occasionally small calcification; (3) the thymus has muscular and uniform density, enhanced CT shows mild enhancement (Fig. 1.4). The density may be uneven, but there is no obvious nodular enhancement; (4) the interface between thymus and sternum, aortic arch, and leading edge of the heart is wide, but there is no erosion and wrapping of adjacent structures, and the boundary between thymus and surrounding normal structures is clear, no lymphadenopathy and pleura and pericardium are involved.
1.5
Differential Diagnosis
Thymic hyperplasia is easily confused with thymoma. Thymic hyperplasia is usually manifested by diffuse, symmetric enlargement of the thymus, a smooth contour, scattered fat and soft-tissue elements, normal vessels, and preserved adjacent fat planes. Thymoma occurs in adults. The mass is nodular or lobulated, with heterogeneity (i.e., hemorrhage or necrosis), or calcifications. It can be associated with pleural and pericardial involvement and lymph node metastasis. On CT enhanced scans, thymoma is homo-
geneous or heterogeneous mass, and the enhancement was obvious; thymic hyperplasia was slightly enhanced or not. Hormone therapy trials are also a method of identification. After hormonal treatment, the normal thymus and hyperplastic thymus often atrophy, and can increase again after stopping treatment, while thymoma does not respond to hormonal treatment. All thymic hyperplasia are quadrilateral (with or without biconvex margins), triangular, or bilobed. Bipyramidal morphology and the presence of gross intercalated fat are each pathognomonic for thymic hyperplasia. Epithelial thymic tumors and other tumors involving the thymus do not demonstrate microscopic fat by histopathology. Therefore, the diagnosis of microscopic fat through MRI is extremely helpful to distinguish thymic hyperplasia from tumor. In 2007, Inaoka et al. demonstrated that chemical shift MRI may be used to detect the presence of microscopic or intravoxel fat within thymic lesions and thereby distinguish thymic hyperplasia from thymomas and lymphomas [9]. Forty-one patients whose thymic lesions were seen at chest computed tomography were assessed, and assigned to a hyperplasia group (n = 23, 18 with hyperplastic thymus associated with Graves’ disease and 5 with rebound thymic hyperplasia) and a tumor group (n = 18, 7 with thymomas, 4 with invasive thymomas, 5 with thymic cancers, and 2 with malignant lymphomas). All patients in hyperplasia group had an apparent decrease in thymus gland signal intensity at chemical shift MR imaging, while no decrease in thymus gland signal intensity was shown in patients of tumor group. Therefore, mediastinal MRI is a reasonable choice if bipyramidal, bilobed, triangular, or quadrilateral morphology is found, in the absence of obvious intercalated fat throughout the lesion on CT, and the lesion appears mass-like. Mediastinal MRI including chemical shift MR imaging is to distinguish between thymic hyperplasia and thymic tumors, whether thymoma or lymphoma.
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Fig. 1.4 Chest CT image in a 41-year-old woman showed a triangular or arrowhead-shaped thymus at the level of the aortic arch. Contrast- enhanced CT scan showed slightly enhanced and vascular shadow (red arrow)
1.6
Treatment
Pediatric patients with thymic hyperplasia can be treated with oral hormone as diagnostic therapy. Generally, thymus began to shrink after 1 week. However, the treatment of giant thymic hyperplasia remains controversial. The hormone therapy has no obvious effect, which may be related to the thymus being too large and insensitive to drugs. Studies have shown that thymectomy in children, especially infants less than 1-year-old, can cause a decrease in peripheral blood T lymphocytes. So thymectomy should be avoided as much as possible. Complete surgical resection is still an important method for the treatment of thymic hyperplasia, especially for patients with respiratory and circulatory system symptoms or other emergency conditions. Surgical treatment should be carried out as soon as possible to improve the symptoms of patients. Children who do not respond to hormonal therapy still need surgery after a little older.
1.7
Case Analysis
1.7.1 Case 1 A 30-year-old man complained of chest tightness for more than 3 months. Chest CT: Multiple cystic low-density lesions were seen in the thymus area and around the superior vena cava, and the enhanced scan showed homogeneous enhancement (Fig. 1.5a–f). [Diagnosis] Thymic hyperplasia. [Diagnosis basis] Multiple cystic low-density lesions were seen around the thymus region and the superior vena cava. The lesions in the thymus region were pear shaped, conforming to the shape of the thymus. Enhanced scans showed homogeneous enhancement of lesions. The above features combined with patient age need to consider the possibility of thymic hyperplasia. The patient underwent medi-
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Fig. 1.5 (a–f) Chest CT image of a 30-year-old man complained of chest tightness for more than 3 months
astinoscopy. Intraoperatively, solid hyperplastic lymph node tissue was found in the posterior lower part of subclavian artery. Pathology showed that most of the tissues were fatty fibers and irregular blood vessels, in which small pieces of hyperplastic thymus tissue were seen (Fig. 1.6). Immunohistochemistry demonstrated positivity for CK, CD3 (Fig. 16b), CD20, CD21 (FDC), CD68, CD34 (vascular), and CD31 (vascular), and negativity for D2–40 and CK19. It is consistent with thymic follicular hyperplasia. [Analysis] The thymus is sensitive to any kind of bodily stress, including systemic infection, tumors, surgery, and chemotherapy, and responds with rapid atrophy, regrows to its original size, or even larger. The thymus is disproportionately larger in infants but gradually replaced by fat and involutes throughout maturation. Nevertheless, the thymus maintains its ability to grow back at any time and age. The most common morphologic feature of thymic hyperplasia was pyramidal shape, seen in 80% of the patients.
Thymic lymphoid hyperplasia refers to the presence of thymic tissue with lymphoid germinal centers in the thymic medulla. It is observed in a number of autoimmune diseases, most commonly myasthenia gravis, being seen in up to 65% of myasthenia gravis patients. To identify features that can differentiate true hyperplasia from lymphoid hyperplasia, the imaging characteristics of pathologically proven thymic hyperplasia were investigated by Araki et al. [10]. CT attenuation of lymphoid hyperplasia was found to be significantly higher than that of true hyperplasia, with the optimal threshold of greater than 41.2 HU for differentiating lymphoid hyperplasia from true hyperplasia. Other measurements, including length, thickness, diameters, and qualitative features, did not significantly differ between the two subtypes of thymic hyperplasia. The higher CT attenuation of lymphoid hyperplasia patients is not due to age differences, but likely reflects the histologic features of the entity composed of lymphoid follicles. The results were
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Fig. 1.6 H&E staining, 400×. Figure 1.8 Immunohistochemically, the CD3 was positive (400×)
somewhat counterintuitive, by pathologic definitions, true hyperplasia is defined as enlargement of the thymus gland, determined by weight and volume, beyond the upper limit of normal for that particular age, whereas lymphoid hyperplasia refers to the presence of an increased number of lymphoid follicles and may or may not be associated with enlargement of the thymus. Given the description, one might expect that the thymic gland with true hyperplasia is larger than the gland with lymphoid hyperplasia; however, their results showed no difference. Thymic hyperplasia mainly depends on histological diagnosis. Thymic hyperplasia can be diagnosed once germinal center and/or lymphoid tissue hyperplasia and lymphoid follicle formation of medullary B cells are found in the medulla.
yellow tissue was sent for examination. The tissue was in an intact capsule. Histologically, it was confirmed that the tissue was thymus, which was consistent with thymus hyperplasia. [Analysis] Myasthenia gravis is an autoimmune disorder of the neuromuscular junction characterized by muscle weakness, often initially involving the extrinsic ocular muscles and subsequently resulting in generalized myasthenia gravis in two-thirds of patients. Myasthenia gravis is often associated with thymic abnormalities. At onset, thymic lymphoid hyperplasia and thymoma can be found in up to 65% and 15% of patients, respectively. The association between lymphoid hyperplasia and myasthenia gravis has been well established and studied. Nicolaou et al. studied 45 patients with myasthenia gravis who underwent thymectomy and reviewed CT findings of 22 patients with lymphoid hyperplasia [11]. Among them, 10 had normal thymic tissue on 1.7.2 Case 2 CT, 7 had a diffusely enlarged thymus (defined as >1.3 cm thickness of the lobe for patients >20 years old), and 5 had a A 26-year-old man was admitted to the local hospital half a focal mass. In Araki et al. study [10], 7 of 10 patients with year ago due to blepharoptosis (both sides), dysphagia, labo- myasthenia gravis had lymphoid hyperplasia, whereas three rious breathing, and weakness of limbs. He was considered had true hyperplasia. All three patients with myasthenia and “myasthenia gravis, thymoma” and treated with double- true hyperplasia had a history of steroid use, which may filtration plasmapheresis, ventilator-assisted breathing, etc. explain the result. He was discharged after the symptoms improved and treated Thymic lymphoid hyperplasia is seen in only 1–2% of with bromopyrimidine and dexamethasone. He was admitted normal individuals but is a common finding in patients with half a month ago because of shortness of breath. autoimmune diseases. In addition to myasthenia gravis, sevChest CT: A soft tissue lesion was found in the anterior eral other autoimmune diseases are associated with the mediastinum and slightly enhancement under the enhanced development of thymic lymphoid hyperplasia. These include CT scan (Fig. 1.7a–f). Graves’ disease, progressive systemic sclerosis, rheumatoid [Diagnosis] Thymic hyperplasia arthritis, and systemic lupus erythematosus. In fact, the diag[Diagnosis basis] A young man had symptoms of myas- nosis of thymic lymphoid hyperplasia cannot be made outthenia gravis. Chest CT scan showed soft tissue lesion con- side the context of autoimmune disease. The presence of taining fat density in the thymus region. The enhanced scan medullary lymphoid follicles is well documented in autoimwas slightly enhanced. The possible diagnosis is thymic mune diseases. This suggests an autoimmune-mediated basis hyperplasia. Intraoperatively, a piece of gray-red and gray- for thymic lymphoid hyperplasia.
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Fig. 1.7 (a–f) Chest CT image of a 26-year-old man
References 1. Shimosato Y, Mukai K. Tumors of the mediastinum: atlas of tumor pathology, 3rd series, vol. 21. Washington, DC: Armed Forces Institute of Pathology; 1997. p. 158–68. 2. Yarom N, Zissin R, Apter S, et al. Rebound thymic enlargement on CT in adults. Int J Clin Pract. 2007;61:562–8. 3. Budavari AI, Whitaker MD, Helmers RA. Thymic hyperplasia presenting as anterior mediastinal mass in 2 patients with Graves’ disease. Mayo Clin Proc. 2002;77:495–9. 4. Sari I, Binicier O, Birlik M, et al. Thymic enlargement in a patient with juvenile idiopathic arthritis during etanercept therapy. Rheumatol Int. 2009;29:591–3. 5. Smith KY, Valdez H, Landay A, et al. Thymic size and lymphocyte restoration in patients with human immunodeficiency virus infection after 48 weeks of zidovudine, lamivudine, and ritonavir therapy. J Infect Dis. 2000;181:141–7.
6. Defriend DE, Coote JM, Williams MP, et al. Thymic enlargement in an adult following a severe infection. Clin Radiol. 2001;56:331–3. 7. Song YS, Won JK, Kim MJ, et al. Graves’ patient with thymic expression of thyrotropin receptors and dynamic changes in thymic hyperplasia proportional to Graves’ disease. Yonsei Med J. 2016;57:795–8. 8. Levine GD, Rosai J. Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol. 1978;9:495–515. 9. Inaoka T, Takahashi K, Mineta M, et al. Thymic hyperplasia and thymus gland tumors: differentiation with chemical shift MR imaging. Radiology. 2007;243:869–76. 10. Araki T, Sholl LM, Gerbaudo VH, et al. Imaging characteristics of pathologically proven thymic hyperplasia: identifying features that can differentiate true from lymphoid hyperplasia. AJR Am J Roentgenol. 2014;202:471–8. 11. Nicolaou S, Muller NL, Li DK, et al. Thymus in myasthenia gravis: comparison of CT and pathologic findings and clinical outcome after thymectomy. Radiology. 1996;201:471–4.
2
Thymic Cyst Dan Cheng and Song Zhang
Thymic cysts are rare lesions that account for 3–5% of all mediastinal masses and represent approximately 1–2% of anterior mediastinal tumors.
2.1
Classification
The thymic cysts may be congenital or acquired. The congenital thymic cysts originate from embryonic remnants and may be found along the thymopharyngeal duct, which extends from the upper neck to the anterior mediastinum. The congenital thymic cysts occur rarely in the posterior mediastinum or near the diaphragm. The congenital thymic cysts are typically unilocular and contain clear fluid within the thin wall. They are mostly asymptomatic and are discovered incidentally during the first two decades of life. In contrast, the acquired thymic cysts (also known as multilocular thymic cysts) are usually multilocular and contain turbid fluid or gelatinous material due to the hemorrhage or infection. The acquired thymic cysts have been reported to be associated with radiation therapy for Hodgkin’s disease, thymic tumor, thymic hyperplasia, thoracostomy or chest trauma, and human immunodeficiency virus (HIV) infection.
2.2
Clinical Features
Thymic cysts can occur in the neck and mediastinum, and are more common in the upper mediastinum. Cervical thymic cysts are most common at the age of 10–20 years, and mediastinal thymic cysts are more common at the age of
30–60 years. Clinically, it can also be ectopic, such as in the middle posterior mediastinum and anterior inferior mediastinum. Usually, small thymic cyst causes no clinical symptoms and often be found in physical examination. It was reported that 13–40% of the patients have clinical symptoms because of the adjacent mediastinum structure were oppressed by the accumulation of fluid and the increasing volume of cyst. In a study performed by Suster and Rosai on 18 patients, seven patients presented with chest pain or discomfort. Symptoms may be due to the enlargement of the cysts secondary to fluid accumulation. Dysphagia may occur if the esophagus is compressed; chest tightness, cough, and dyspnea may occur if the trachea is compressed; and palpitation may occur if the heart is compressed. If the cyst breaks into the pericardium, it may cause cardiac tamponade. Some cases may cause acute symptoms due to the rapid increase of cyst due to the increase of osmotic pressure or intracystic hemorrhage caused by degeneration. Unlike thymic solid tumors, thymic cysts are rarely associated with myasthenia gravis.
2.3
Histopathology
The pathological changes of thymic cysts are serous fluid or hemorrhage in the cysts, without malignant tendency. Microscopically, a unilocular cyst is characterized by a unique cavity lined by flattened epithelial cells surrounded by a thymic parenchyma. In case of multilocular thymic cysts, several cystic spaces are separated by thick walls containing dense lymphoid tissue. The cyst wall has thymic tissue, which is the basis for the diagnosis of thymic cysts.
D. Cheng Department of Respiration, Central Hospital of Haining, Zhejiang Province People’s Hospital Haining Hospital, Haining, China
2.4
S. Zhang (*) Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China
The diagnostic methods of thymic cysts include chest X-rays, ultrasound, CT, and magnetic resonance imaging (MRI). Chest radiography can find asymptomatic lesions and can
Radiographic Features
© Science Press 2021 S. Zhang (ed.), Diagnostic Imaging of Mediastinal Diseases, https://doi.org/10.1007/978-981-15-9930-9_2
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initially determine the scope of the lesion. Thyroid scan can determine the relationship between the lesion and the thyroid gland. Ultrasound diagnosis can find the cyst wall and cyst fluid. Chest CT scan can clearly identify the cystic characteristics of the mass and determine the size and extent of the lesion, unilocular or multilocular, intracapsular density, etc., and the relationship between the mass and adjacent mediastinal structures and whether it is associated with thymic hyperplasia can be clarified. MRI is particularly advantageous in showing the relationship between thymic cysts and surrounding tissues, and can be used as a supplement to CT examinations. Thymic cysts generally appear as unilocular or multilocular cystic lesions with smooth and well-circumscribed border, round or round-like (Fig. 2.1), and some have mass
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effect. The lesions are often located at the midline structure, and there may be no obvious thymic tissues around them. Some huge individuals can extend to both sides of the thorax (Fig. 2.2). On CT imaging, these lesions have no solid components, demonstrate thin, barely perceptible walls, which can be deformed with the change of mediastinal morphology during deep breathing (Fig. 2.3). The density (or signal) of the contents inside the capsule is uniform, which equals the water sample (0–20 HU). There is a fat gap between the adjacent mediastinal structure and cyst and do not enhance with intravenous contrast administration (Fig. 2.4). Occasionally, internal septations or mural calcifications could be seen, and the internal contents of the cyst may be proteinaceous or hemorrhagic, which causes
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Fig. 2.1 A 52-year-old man found a round, well-defined thymic cyst in the left anterior superior mediastinum
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Fig. 2.2 A 54-year-old man found a giant anterior mediastinal cyst. Surgery showed that the cyst was close to the pericardium and pulmonary artery and extended to both sides of the thoracic cavity. The size
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was 40 × 30 × 20 cm, the capsule was intact and severely adhered to the surrounding pleura. The cyst contained 2400 ml of watery transparent liquid. Postoperative pathological diagnosis was thymic cyst
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Fig. 2.3 A 59-year-old woman with a thymic cyst showed a thin cystic wall on the chest CT. Differences in inspiratory amplitudes can cause changes in the shape of the cyst. This is a characteristic of some thymic cysts
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Fig. 2.4 A 51-year-old man with a thymic cyst. The CT attenuations of the three-phase dynamic scan were 32.6, 31.5, and 30.7 HU, respectively
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Fig. 2.5 A 30-year-old woman found cystic lesions in the left anterior mediastinum. Calcification was seen at the lower edge of the cyst wall, and no enhancement was seen in the enhanced scan. Gross specimens of the operation showed a single cyst with a size of 7 × 5 × 3.5 cm. The
capsule contains sebaceous material and the thickness of the capsule wall is 0.3–1 cm. The pathological diagnosis was thymic cyst, and a large amount of residual thymic tissue was seen around the cyst wall
the attenuation of the soft tissue mass and results in a diagnostic dilemma. The negative CT attenuation in the cyst is one of the characteristics, which is related to the residual thymic tissue (containing fat) in the cyst and the degenerative thymic cyst surrounding the mediastinal adipose tissue (Fig. 2.5). The CT attenuation of the cystic fluid will increase while the cyst is accompanied by bleeding or high protein content. It can be occasionally misdiagnosed as a solid mass (Fig. 2.6). CT features of idiopathic multilocular thymic cyst were investigated by Choi et al. in eight patients [1]. They reported that typical appearance of multilocular thymic cysts is heterogeneous, unilocular, or multilocular cystic mass, and often with a soft-tissue attenuation component, and well-defined wall sometimes with calcifications. Their conclusion was that CT was not helpful to distinguish neoplastic from nonneoplastic soft tissue components. Araki et al. reported that 18 patients with pathologically confirmed intrathymic cysts who underwent thymectomy and had preoperative chest CT available for review [2]. Among the 11 patients with contrast-enhanced chest CT, the mean CT attenuation of the cysts was 38 HU (range 6–62 HU), while in 7 patients with unenhanced CT the value was 45 HU (range 26–64 HU). In 15 out of 18 patients (83%), the CT attenuation was >20 HU, the threshold usually used to differentiate fluid from soft tissue. Ackman et al. reported that true thymic cysts ranged in attenuation from −20 to 58 HU, with a mean attenuation of 23 HU [3].
ferential diagnosis method. Thymoma can be mildly and evenly enhanced. Scan for thymic masse should be routinely enhanced to reduce misdiagnosis. In general, a small lesion that occurs in the thymus area is more likely to be cyst than thymoma. Thymic cyst must also be distinguished from cystic teratoma. Cystic teratoma can contain fatty components, calcifications, or even tooth-like structures. Other cystic masses that may appear in the anterior superior mediastinum are cystic lymphangioma, bronchial cyst, and pericardial cyst. Preoperative identification is often difficult, especially in those cases where the normal thymus has completely deteriorated.
2.5
Differential Diagnosis
High-density small thymic cyst and smaller thymoma are indeed difficult to distinguish in terms of morphology and density during CT scan, but enhanced scan can provide a dif-
2.6
Treatment
Small mediastinal cysts, including also the thymic cysts, are without any clinical manifestations, do not require any treatment. The bigger cysts in the mediastinum, with compressed structures around, give different clinical manifestations, and need therapeutic treatment like puncture or extirpation of the cyst. There has not been a consensus about the surgical therapeutic approach for the treatment of mediastinal cysts. The puncture of a bigger cyst can release symptoms, but the persistence of the epithelium that produces fluids can fulfill the cyst again. In addition, there is also the possibility of infection of the cyst and serious problems with mediastinal infection. The treatment of thymic cysts is based on surgical resection and must be as complete as possible. In Suster and Rosai’s study of 18 cases, two patients presented a recurrence of the cyst due to incomplete surgical resection. For smaller mediastinal cysts, a video-assisted surgical approach may be appropriate as minimally inva-
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Fig. 2.6 A 48-year-old woman found a solid mass in the right anterior mediastinum with obvious calcification and no enhancement on multipoint enhanced scans (four-phase dynamic scan were 58.2, 55.9, 51.6, and 52.5 HU, respectively). The pathological diagnosis was thymic cyst
sive. The whole pathologic substrate with minimally invasive surgery can be removed. Surgical excision, via median sternotomy, thoracotomy, or video-assisted techniques is necessary for definitive diagnosis, treatment, and elimination of recurrence.
2.7
Case Analysis
2.7.1 Case 1 A 16-year-old man found a mediastinal mass for 5 days on physical examination. Chest CT: A oval cystic mass with clear borders occupied the left anterior superior mediastinum (Fig. 2.7a–d). [Diagnosis] Thymic cyst [Diagnosis basis] This is an oval-shaped low-density mass in the left anterior mediastinum, which is close to the
density of water samples. It is considered as a cystic lesion and the cyst wall is thin. Linear and speckled calcification (red arrow) can be seen. No enhancement is seen in the enhanced scan. Thymic cysts are considered. The patient underwent resection of the left anterior mediastinal tumor. Postoperative pathology showed that residual thymic tissue was visible in the cyst wall of the submitted tissue. The cyst cavity contained eosinophils with calcification, consistent with thymic cyst. [Analysis] Mediastinal cystic mass is well-marginated, round, epithelium-lined lesions that contain fluid. Cysts account for 15–20% of all mediastinal masses and occur in all compartments of the mediastinum. The most common cystic lesions include bronchogenic cysts, pericardial and neurenteric cysts, esophageal duplication cysts, thymic cysts, meningocele, cystic teratoma, and lymphangioma. Thymic cysts need to be distinguished from cystic teratomas, foregut cysts, and pericardial cysts.
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Fig. 2.7 (a–d) Chest CT of a 16-year-old man found a mediastinal mass on physical examination
Thymic cysts with mural calcification are easily misdiagnosed as cystic teratomas. Teratomas occur in the anterior superior mediastinum, and can also be a thin-walled cyst. However, the cyst wall of teratomas is generally thicker than that of thymic cysts. Teratomas may contain fat components, soft tissue components, liquid components, calcifications, or tooth-like structures. The mediastinal foregut cysts originate from the embryonic foregut and are the most common type of mediastinal cysts (Fig. 2.8a–d). They are divided into bronchogenic cysts, esophageal cysts, and gastrointestinal cysts based on the components of the cyst wall and the lining cells. Bronchogenic cysts are congenital lesions, which originated from abnormal budding of the embryonic foregut. Most bronchogenic cysts occur in the lungs and mediastinum and rarely derive from the diaphragm. The location of occurrence of bronchogenic cysts depends on their timing of development during embryogenesis. Mediastinal bronchogenic cysts are divided into paratracheal, carinal, paraesophageal, hilar, and miscellaneous subtypes. Its common location is the posterior mediastinum and the subcarinal region. It may be
attached to the carina, but does not communicate with the tracheobronchial tree. Typically, the lining of the cyst is composed of respiratory epithelium, sometimes with squamous metaplasia. The most reliable criterion for bronchogenic cyst is the presence of cartilage in the wall. The water-attenuation and soft tissue-attenuation represent two different radiologic patterns of bronchogenic cysts. Esophageal cysts are mostly located near the esophagus. Most patients are asymptomatic, and a few have difficulty swallowing due to compression of the esophagus, and some patients may be misdiagnosed with asthma or chronic bronchitis due to chronic cough. Gastrointestinal cysts are composed of gastric epithelium alone or together with intestinal mucosa, whereas entirely intestinal mucosa-lined cysts are extremely rare. Among them, gastric mucosal epithelial cells can have secretory functions, leading to peptic ulcers. The imaging characteristics of gastrointestinal cysts are basically consistent with bronchogenic cysts, but gastrointestinal cysts are rarely calcified. Pericardial cysts were first described in 1837 as diverticula extending from the pericardium. These lesions are uni-
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Fig. 2.8 (a–d) A 38-year-old man complained of intermittent chest tightness and chest pain for more than 2 years, and found a mediastinal mass for 1 year. Chest CT showed a uniform cystic mass in the anterior superior mediastinum and no enhancement. Pathology showed that the cyst wall was lined with gastric epithelium, intestinal epithelium, and
pancreatic duct epithelium. A small amount of pancreatic tissue was found in the cyst wall fibrous tissue, and a small amount of atrophic thymus tissue was outside the cyst wall. The pathological diagnosis was foregut cyst
locular and contain transparent water-like fluid, with the occasional addition of blood and necrotic cystic content; the cyst wall is composed of connective tissue lined by mesothelial cells. Classically, pericardial cysts are located in the right cardiophrenic angle (51–70%), compared to that in the left cardiophrenic angle (28–38%) and rarely in other mediastinal sites. They are rare and often asymptomatic. Symptoms may be similar to more common causes of chest pain or dyspnea such as acute coronary syndrome or pulmonary embolism. Emergency physicians should consider mediastinal masses in the differential diagnosis of chest pain. In this case, pericardial cysts should be considered because of the risk of tamponade, sudden cardiac death, or other life- threatening complications. When the thymic cysts are large in size, they grow into strips or casts squeezed by adjacent tissues, and drop to a lower position due to gravity, even at the cardiophrenic angle (Fig. 2.9). Pericardial cysts can be similar to thymic cysts in CT or MRI, but the upper part is not connected to the thymus, and mural calcification is less common, and they are not all round, and can take different shapes at different periods.
2.7.2 Case 2 A 59-year-old man was examined and found a mediastinal mass. Chest CT: Irregular cystic masses were seen in the left anterior superior mediastinum with clear borders and uniform density. The four-phase attenuations were 32.1, 24.1, 42.0, and 42.3HU (Fig. 2.10). [Diagnosis] Thymic cyst [Diagnosis basis] Anterior mediastinal cystic lesions with full margins and space-occupying effects are possible for thymoma and cysts. Insufficient tension, straight edges, or even partial depression, support the diagnosis of thymic cysts. In view of the mild enhancement of the enhanced scan in this case, the possibility of thymoma needs to be ruled out. Because the cyst of the thymic cyst is thin and the shape of the lesion can change with respiration. Examination of the expiratory phase showed that the lesion was full, the volume increased, and the CT attenuation also changed (Fig. 2.11). The diagnosis of thymic cyst was clear.
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Fig. 2.9 A 69-year-old man with thymic cyst. Chest CT scan showed a low attenuation of the pericardial cystic soft tissue mass adjacent to the anterior mediastinum and anterior chest wall
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Fig. 2.10 Chest CT images of a 59-year-old man
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Fig. 2.11 The exhalation phase CT showed that the lesion was full, the volume increased, and the CT attenuation also changed
[Analysis] Locations of Oval shape, smooth contour, midline without visible adjacent thymic tissue, calcification, mass effect, or septa are the most frequent qualitative imaging features of intrathymic cyst. McErlean et al. retrospectively reviewed preoperative CT imaging for 66 patients, who had undergone thymectomy for benign thymic lesions or early-stage malignant thymic neoplasms [4]. Twenty- eight benign thymic lesions were studied, including 10 benign thymic cysts. They concluded that intralesional fat, midline location, and triangular thymic shape were more frequently found in “benign thymic lesions.” The midline location was one of the most common findings of intrathymic cyst in the present cohort, accounting for 61% of the cases. Triangular shape or intralesional fat was not found in the present cohort, probably because these were the findings associated with other benign entities, such as thymolipoma, thymic hyperplasia, or benign thymus rather than cyst. Therefore, these CT features alone are difficult to distinguish between intrathymic cysts and thymic tumors, especially low-grade thymoma. There are several methods to identify thymic cysts. If the CT attenuation of the enhanced scan does not change, it can be diagnosed as a cyst. However, the CT attenuation of small lesions is occasionally slightly enhanced, which is often difficult to distinguish. Thymoma is a solid tumor with a ten-
dency to swell outward, and the edges are mostly swollen. Thymic cysts have thin walls, and sometimes due to inhalation, the cysts are compressed, deformed, and shrink in volume. If the normal scan and the enhanced scan have different inspiratory amplitudes, the lesion’s morphology changes after two examinations, which can be diagnosed as a cyst. In addition, the inspiratory phase and the expiratory phase are scanned respectively. Due to the thin wall of the cyst, the morphology of the two scans will almost change, and the density and cyst position may sometimes change, which cues cyst.
References 1. Choi YW, McAdams HP, Jeon SC, et al. Idiopathic multilocular thymic cyst: CT features with clinical and histopathologic correlation. AJR. 2001;177:881–5. 2. Araki T, Sholl LM, Gerbaudo VH, et al. Intrathymic cyst: clinical and radiological features in surgically resected cases. Clin Radiol. 2014;69:732–8. 3. Ackman JB, Verzosa S, Kovach AE, et al. High rate of unnecessary thymectomy and its cause. Can computed tomography distinguish thymoma, lymphoma, thymic hyperplasia, and thymic cysts? Eur J Radiol. 2015;84:524–33. 4. McErlean A, Huang J, Zabor EC, et al. Distinguishing benign thymic lesions from early-stage thymic malignancies on computed tomography. J Thorac Oncol. 2013;8:967–73.
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Thymic Epithelial Tumor Cheng-sen Cai and Song Zhang
Thymic epithelial tumors are rare malignancies of thymic origin and include thymoma, thymic carcinoma, and thymic neuroendocrine tumors.
3.1
Epidemiology
Thymic epithelial tumors are rare malignant tumors that account for 0.2–1.5% of all malignancies, 20% of adult mediastinal tumors, and 47% of anterior mediastinal tumors. They may be related to EB virus infection, ionizing radiation, and genetic genes. Thymoma is the most common primary malignancy of the anterior mediastinum and the most common thymic epithelial tumor. The incidence of thymoma is 1–5 cases per million people per year in the United States, but the incidence of Asian and African Americans is higher than that of Hispanics and whites. Men and women are equally affected. The incidence of thymoma increases with advancing age, patients older than 40 years are most commonly affected, although the incidence starts to decline after the age of 60 years. Thymoma is slow-growing neoplasms that may exhibit aggressive behavior, such as invasion of adjacent structures and involvement of the pleura and pericardium, but distant metastases rarely occur. Thymic carcinoma represents approximately 20% of thymic epithelial tumors. The average age of patients at presentation is 50 years. Contrary to thymoma, thymic carcinoma tends to show aggressive features such as local invasion, intrathoracic lymphadenopathy, and distant metastases. 50–65% of patients have distant metastases at diagnosis. C.-s. Cai Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China S. Zhang (*) Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, China
Neuroendocrine tumor is the least common, accounting for 2–5% of all such lesions. Most neuroendocrine tumors of thymic origin are carcinoids. Approximately 0.4% of all carcinoids come from the thymus. Similar to thymic carcinoma, thymic neuroendocrine tumors may demonstrate aggressive behavior such as invasion of adjacent structures and mediastinal lymph node involvement, the latter of which is present in 50% of patients at diagnosis.
3.2
Classification
Historically, many staging systems have been used for thymic epithelial tumors, including both non-TNM based and TNM based. Due to the diversity of thymic epithelial tumor morphology, the heterogeneity of tumor cells, and the lack of simple and effective classification of observation indicators, there is no unified basis for its classification method. At least 15 different stage classification systems have been proposed and used clinically to varying degrees, most of which have been derived from data on small groups of patients. The most widely used staging classification is the Masaoka-Koga staging system. In the 1960s, thymomas were classified as non-invasive and invasive. Historically, the morphologic classification has been the most widely accepted during the past several decades. Thymomas were divided by these authors, based on their relative proportion of epithelial cells to lymphocytes and on the shape of the epithelial cells. In 1961, Bernatz et al. classified thymoma into four basic histopathologic variants: lymphocyte-predominant, epithelial-predominant, lymphoepithelial (mixed), and spindle cell thymoma. This classification essentially constituted a variation of a similar formula proposed by Lattes and Jonas 4 years earlier, in which thymomas were also divided into 4 variants (predominantly lymphocytic, predominantly epithelial, and predominantly spindle cell). However, it also included a category of rosette-forming thymoma. The Bernatz et al. classification
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and variants thereof have come to be known collectively as the traditional classification of thymoma. The first staging system was proposed by Bergh et al. [1] which differentiated thymoma according to the presence of symptoms, the tumor extent and histology, and designed a three-stage classification system. Stage I thymoma is intact capsule or growth within the capsule. Stage II thymoma is pericapsular growth into the mediastinal fat tissue. Stage III thymoma is invasive growth into the surrounding organs, intrathoracic metastases, or both. A complete tumor resection (R0), (commonly observed in stages I and II), was associated with a longer survival. Postoperative radiotherapy was offered to incompletely resected patients and mostly stage II and III ones. Minor modifications were made to the Bergh staging system by Wilkins and Castleman in 1979 [2], including mediastinal pleura or pericardial invasion in stage II. Tumor invasiveness was demonstrated as an adverse prognostic factor, and it may guide postoperative radiotherapy. The completeness of resection was proposed as the strongest prognostic factor. In a series study of 103 patients with thymoma, the 10-year survival rates were 67% for encapsulated tumors and 40% for invasive lesions. There are some disadvantages for this system: the actual site of intrathoracic metastasis, inadequate description of invasion, too broad classification of stage III, and lack of representation of lymphogenous or hematogenous metastasis. Despite apparently good reproducibility among pathologists for applying the traditional histopathologic classification of thymoma, the various types did not show good correlation with the clinical behavior of the tumors and, therefore, were not very useful for prognostication. In 1978, the encapsulated tumors were proposed as benign by Levine and Rosai and that all invasive tumors should be regarded as malignant [3]. The malignant thymoma was further proposed to be subclassified into two types: I— invasive tumors showing the same morphologic features as benign thymoma; II— for tumors displaying overt cytologic features of malignancy (also designated as thymic carcinoma). The Levine and Rosai proposal gained wide acceptance [3], which was used for many years, often in combination with the traditional nomenclature for the various morphologic subtypes of thymoma. Two additional approaches to the classification of thymoma were introduced in 1985. Marino and Muller- Hermelink based on the light microscopical features of normal thymic epithelial cells [4], human thymoma was divided into different types, namely cortical, medullary, and mixed types. In their retrospective study of 58 thymomas and 13 thymic carcinomas, they found malignant invasive character and the occurrence of myasthenia gravis is related to the neoplastic proliferation of the cortical epithelial cells. The tumors composed of cells were thought to be derived from the medulla or of mixed cortical-medullary types that
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were not associated with invasion or metastases. This classification subsequently was modified by Kirchner and Muller-Hermelink to include 2 additional categories [5], the predominantly cortical thymoma (later renamed organoid) and the well-differentiated thymic carcinoma in 1989. The value of this new classification resided in facilitating the correlation between these various morphologic types of thymoma and invasiveness. In 1985, Verley and Hollmann published the 1955–1982 Marie Lannelongue Hospital (Paris, France) experience on surgical management of 200 thymoma [6]. They compared clinical stages and histologic types in different aspects, including survival. Clinical stages were defined as follows: Stage I—no invasiveness, total excision; Stage II—localized invasiveness (no more than two mediastinal structures); Stage III—largely invasive, with or without distant tumorous grafts, lymph node deposits, or metastases. Four histologic types included spindle cell thymoma, lymphocyte-rich thymoma, differentiated epithelial thymoma (roughly corresponding to epithelial-rich thymoma according to the traditional classification), and undifferentiated epithelial thymoma (corresponding to thymic carcinoma). Histologic typing indicated a good correlation between the degree of differentiation of the tumors and prognosis. They pointed out that although invasiveness often paralleled histologic typing, they both seemed to represent distinct and independent parameters with separate prognostic significance. The associated syndromes were no longer an adverse factor in the prognosis of thymoma. The clinical course of thymoma was firstly highlighted by Masaoka [7], usually indolent, which may be characterized by local invasion, infiltration, and finally by distant spread with lymphogenous/hematogenous metastases. The four- stage system proposed by Masaoka in 1981 was based on the Osaka University experience with 93 thymoma patients during 1954–1979. Establishing a correct stage at the beginning of the treatment was suggested to be helpful for selecting the appropriate therapy and improve survival. One of the main prognostic factors is invasiveness, along with the completeness of surgical resection. Clinical stages were defined: Stage I—macroscopically encapsulated and microscopically no capsular invasion; Stage II—(1) macroscopic invasion into surrounding fatty tissue of mediastinal pleura, or (2) microscopic invasion into capsule; Stage III—macroscopic invasion into neighboring organ; Stage IVa—pleural or pericardial dissemination; Stage IVb—lymphogenous or hematogenous metastasis. Koga et al. proposed a revised Masaoka staging system in 1994. The stages were as follows: Stage I—grossly and microscopically completely encapsulated; Stage II—(1) microscopic transcapsular invasion, or (2) macroscopic invasion into thymic or surrounding fatty tissue, or grossly adherent but not breaking through mediastinal pleura or pericardium; Stage III—macroscopic invasion
3 Thymic Epithelial Tumor
of neighboring organ (i.e., pericardium, great vessel, or lung); Stage IVa—pleural or pericardial dissemination; Stage IVb—lymphatic or hematogenous metastasis. According to the Masaoka-Koga system, survival curves demonstrated no significant difference between stages I and II, and between stages III and IV either. Tumor-related death and recurrences were more frequent in advanced stages. A simplified our- staged staging system was concluded to only differentiate between invasive (stage III/IV) and noninvasive (stage I/II) thymomas. The Masaoka-Koga staging system is still the most commonly used and the International Thymic Malignancy Interest Group (ITMIG) had established it as the unified staging system for use in 2011 until publication of the eighth edition of AJCC/UICC staging manuals. There are limitations of the Masaoka-Koga staging system, including lack of survival difference between stages I and II disease, stage III disease involving invasion of a large range of structures, and a predominantly pathologic staging system that is difficult to apply to clinical staging. The first classification system developed by the World Health Organization (WHO) Consensus Committee in 1999 classified thymomas into six separate subtypes (A, AB, B1, B2, B3, and C) based on morphologic features of the neoplastic epithelial cells and the lymphocyte–epithelial cell ratio. There are two major types of thymoma, depending on whether the neoplastic epithelial cells and their nuclei showed a spindle or oval shape (designated type A) or a round epithelioid appearance (designated type B). Type AB is designated for tumors that show a combination of these 2 cell types. Based on the proportional increase (in relation to the lymphocytes) and emergence of atypia of the neoplastic epithelial cells, type B thymomas were subdivided further into 3 subtypes, designated B1, B2, and B3. Type C thymoma was regarded as a tumor showing overt cytologic features of malignancy (i.e., thymic carcinoma). Therefore, the morphologic basis for this classification was essentially similar to that of the traditional classification presented more than 40 years earlier. A revised scheme published in 2004 relocated type C (thymic carcinoma) to a separate category. In 2015, the WHO classification of thymic tumors corrected the view that thymoma is a benign tumor. Except for micronodular and microscopic thymomas, all major thymoma subtypes can behave in a clinically aggressive fashion and therefore should no longer be called benign tumors, irrespective of tumor stage. The high- and low-risk groups were divided according to type, B2, and B3 or types A, AB, and B1. Yamakawa et al. translated the Masaoka system into a tumor, node, metastasis (TNM) system in 1991 (based on 207 patients). There is no modification for the T descriptor followed the Masaoka criteria. Anterior mediastinal lymph nodes around the thymus were deemed the primary lymph nodes in thymoma, and classified as N1. Finally, tumors
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were classified M0 or M1 according to the absence/presence of hematogenous spread. Prognosis correlating to size was not found. Tsuchiya et al. evaluated the utility of the Yamakawa/Masaoka TNM and staging system and proposed a modification proposed based on experience with 16 thymic carcinomas in 1994 [8]. Although the N descriptor was the same as that of the Yamakawa system, tumors penetrating through the mediastinal pleura or pericardium were classified as T3 category. A much greater role for nodal involvement was considered in this stage grouping. A wide separation in the survival curves was found between stages I and III–IV and between stages III and IV, although this was not statistically significant in the small series. World Health Organization (WHO) proposed another TNM-based classification in 2004. The definition of lymph node categories is the same as that of the other TNM systems. However, the pertinence of nodal grouping from N1 to N3 has not been studied. The main determinants of the T descriptor are tumor invasion through the capsule and into the neighboring organs/ structures. Invasion may be assessed by the surgeon during intervention, or histologically by the pathologist. Bedini et al. proposed a modified TNM system in 2005 (based on a sophisticated analysis of 127patients) [9], which was named the Istituto Nazionale Tumori system. They proposed three-stage groupings: stage I (locally restricted disease) essentially includes Masaoka stages I and II with the exception of mediastinal pleural involvement, stage II (locally advanced disease) includes tumors invading local structures or involving intrathoracic lymph nodes, and stage III (systemic disease) involving cervical nodes or distant extrathoracic sites. Weissferdt and Moran proposed a 3-stage TNM classification for thymic carcinoma based on 33 patients in 2012 [10]. Classification of T1 as a tumor confined to the thymus, T3 as direct extension outside the chest, limiting node categories to intrathoracic and grouping any T3, N1, or M1 as stage III are the major features. The ITMIG and the International Association for the Study of Lung Cancer (IASLC) set out to accomplish a staging system for thymic epithelial tumors, and subsequently joined forces in 2010, partnering to create a Thymic Domain of the Staging and Prognostic Factors Committee (TD-SPFC). ITMIG and IASLC created a collaborative worldwide database involving 105 institutions and 10,808 patients. The IASLC/ITMIG staging system, which has been included in the official eighth edition of AJCC/UICC staging manuals, is based on TNM descriptors. The T stage is derived from Masaoka-Koga staging and is defined by the highest level of invasion of ≥1 structure, with an overall decreased emphasis on tumor encapsulation. The T component was proposed to be divided into four categories by the committee, representing levels of invasion. T1 includes tumors localized to the thymus: T1a is anterior mediastinal fat, and regardless of
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capsular invasion, up to and including infiltration through the mediastinal pleura (T1b). Invasion of the pericardium is designated as T2. T3 includes tumors with direct involvement of lung, chest wall, phrenic nerve, brachiocephalic vein, superior vena cava, or hilar (extrapericardial) pulmonary vessels. Invasion of thoracic aorta, arch vessels, main pulmonary artery, trachea, esophagus, or myocardium is designated as T4. Nodal involvement is divided into no lymph node metastasis (N0), involvement of anterior (perithymic) lymph nodes (N1), and involvement of deep intrathoracic or cervical lymph nodes (N2). Metastases can involve pleural or pericardial nodules (M1a) or intraparenchymal pulmonary nodules or metastases to distant sites (M1b). Stage groups I to IIIB are decided by the T component, whereas stage IVA/B groups are decided by the N and/ or M component.
3.3
Clinical Features
The most common symptoms of thymomas described at clinical presentation include those related to local effects of malignant tumors, including compression and invasion of adjacent structures, which can lead to diaphragmatic paralysis, dysphagia, or superior vena cava syndrome. One-third of patients report chest pain, dyspnea, or cough. Due to the release of hormones, antibodies, and cytokines by the neoplasm, patients may present with systemic symptoms and paraneoplastic syndromes. The most common paraneoplastic syndrome associated with thymoma is myasthenia gravis; 30–50% of patients with thymoma have signs and symptoms of myasthenia gravis, compared to only 10–15% of patients with myasthenia gravis have thymoma. Hypogamma globulinemia and pure red cell aplasia are other important paraneoplastic syndromes, accounting for 10% and 5% of cases, respectively. Various autoimmune diseases may be associated with thymoma, including polymyositis, systemic lupus erythematosus, and myocarditis. The most common symptoms of thymic carcinomas described at clinical presentation include those related to local effects of the tumor, mainly compression and invasion of adjacent structures. In contrast to thymomas, paraneoplastic syndromes rarely accompany thymic carcinomas.
3.4
(smooth or irregular, single lobulated or multi-lobulated); internal density (homogenous or heterogeneous); calcifications; infiltration of surrounding fat; tumor abutting of an adjacent mediastinal structure (≥50% or 10% tumor
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Fig. 3.24 A 54-year-old woman complained of shortness of breath, chest tightness, and chest pain for 1 week. Surgical pathology showed type A thymoma with extensive necrosis, hemorrhage and cystic changes, and no tumor infiltration in the capsule
areas with a moderate infiltrate of immature T cells should prompt classification as type AB thymoma. Type A and B3 thymoma was defined by an organotypic architecture and few or no lymphocytes. Type A thymoma had bland spindle or oval epithelial cells, without features to suggest spindle cell thymic carcinoma. Type B3 thymoma was composed of medium-sized round or polygonal cells with mild atypia. Ki-67 is a well-known histological marker of proliferation used as an index of biological aggressiveness in various solid tumors. It has already been reported that Ki-67 labeling index (LI) correlates with the tumor aggressiveness in thymic epithelial neoplasm. Roden et al. [14] reported that mitotic activity differed between thymic carcinoma and type A or type B3 thymoma. Ki-67 LI in type A thymoma was 0.3–11.0% (median 3.0) and in thymic carcinoma was 12.2– 43.3% (median 23.2%). In differentiating thymic epithelial neoplasms, Ki-67 LI is helpful, with Ki-67 LI 20 years at diagnosis and size >5 cm were associated with a significantly worse prognosis. However, after aggressive multimodal therapy, prognosis is good and survival up to 14 years has been documented by Van der Mieren in 2004.
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Mediastinal synovial sarcoma is a very rare malignant neoplasm presenting as large tumors with advanced stage and poor prognosis. It is very aggressive in nature, with a median survival of 36 months and a 5-year overall survival rate of around 35%.
8.1.9 Case 9 A 26-year-old woman complained of chest tightness and discomfort for half a year. Chest CT: There was a mass in the right anterior mediastinum (Fig. 8.30). [Diagnosis] Embryonal rhabdomyosarcoma [Diagnostic basis] Intraoperatively, most of the capsule was incomplete, and the mediastinal vessels were invaded. The lesion could not be completely removed, and no metastatic lymph nodes were seen in the mediastinum. The cut surface showed that the texture of the tumor was slightly hard and grayish white, with local gel-like changes, and multifocal patchy necrotic areas. The postoperative pathology was embryonal rhabdomyosarcoma.
Fig. 8.29 A 52-year-old woman with right mediastinal synovial sarcoma with ipsilateral pleural metastasis (red arrow), pleural effusion, and left lung metastasis (blue arrow)
Fig. 8.30 Chest CT images of a 26-year-old woman complained of chest tightness and discomfort for half a year
8 Mediastinal Soft Tissue Tumor
[Analysis] Rhabdomyosarcomas are malignant tumors associated with a rhabdomyoblastic phenotype, which can be demonstrated morphologically or by immunohistochemistry for MYOD1 and myogenin. There are currently four types of Rhabdomyosarcomas in 2013 WHO classification of tumors of soft tissue and bone, including embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma. Rhabdomyosarcoma is the most common childhood soft- tissue sarcoma. It displays features of immature skeletal muscle, including the existence of myoblast-like cells, and the expression of myogenic factors such as MyoD and Desmin. Embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma are major subtypes of rhabdomyosarcoma. The largest subtype of rhabdomyosarcoma is embryonal rhabdomyosarcoma accounting for 53% of all rhabdomyosarcoma. Embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma have different genetic mutation signatures. Alveolar rhabdomyosarcoma is characterized by either t(2;13) or t(1;13) chromosomal translocation, which generates PAX3–FOXO1 or PAX7–FOXO1 fusion proteins, respectively. In contrast, embryonal rhabdomyosarcoma frequently have mutations in components of the RAS pathway, such as NRAS mutations, HRAS mutations, or NF1 deletions. Embryonal rhabdomyosarcoma typically occurs in the head and neck region, bladder, or reproductive organs. There
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are no striated muscle cells in the normal histological structure in the mediastinum. Mediastinal rhabdomyosarcoma most commonly occurs in thymus with the ability to differentiate toward myoid tissue, or may occur as a sarcoma-like component, but occasionally can be primary. Its origin may be pluripotent primitive mesenchymal metaplasia into striated muscle cells, or may come from the surrounding skeletal muscle. Mediastinal rhabdomyosarcoma is rare clinically, and the vast majority occurs in the anterior mediastinum, which lacks specificity in imaging. The boundary of the tumor is often unclear, and can involve the middle mediastinum along the vascular space, so it is difficult to remove completely. Treatment includes chemotherapy, radiotherapy, and surgery. The 5-year overall survival rate is ∼43%.
8.1.10 Case 10 A 15-year-old man complained of chest pain for 3 days. Chest CT: A huge cystic mass in the left lower chest, the three-phase CT attentions were 12.92HU, 23.85HU, and 28.93HU, respectively (Fig. 8.31). [Diagnosis] Lymphangioma [Diagnostic basis] A Juvenile male had a huge cystic mass in the left posterior mediastinum. The reconstruction of the coronal plane showed that the mass enveloped the heart
Fig. 8.31 Chest CT images of a 15-year-old man complained of chest pain for 3 days
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and had obvious plasticity. Contrast-enhanced scan showed enhanced margins and linear enhancement (red arrows) within the mass. Postoperative pathology showed cavernous lymphangioma of left thoracic cavity. [Analysis] Vascular anomalies (vascular tumors and vascular malformations) represent a spectrum of disorders from a simple “birthmark” to life-threatening entities. It has been argued whether vascular lesions are developmental malformations or types of neoplasia. Early attempts at classification were based on the pathological features of the lesions without consideration for underlying biologic behavior. Anatomist and obstetrician William Hunter was the first to describe vascular anomalies in the mid-eighteenth century in the context of iatrogenic creation of arteriovenous fistulas by phlebotomists. Dupuytren called them “erectile tumors.” Other nineteenth-century expressions, such as “naevus maternus,” and “stigma metrocelis,” were applied without clear delineation. According to the histological characteristics of congenital vascular anomalies, Virchow, the father of cytopathology, considered these lesions to be vascular tumors and classified them based on channel architecture as angioma simplex, angioma cavernosum, and angiomara cemosum in 1863. He believed that one type could transform into another by either cellular proliferation or vessel dilation. This was a primitive classification system but appropriate for the time. Wegner, after studying with Virchow at the Berlin Pathological Institute, proposed a similar histomorphologic classification of lymphatic swellings: lymphangioma simplex, cavernosum, and cystoides in 1877. Wegner believed that these lesions resulted from either lymphatic inflammation, dilation, and malformation, or endothelial proliferation. It was not until 1982 that Mulliken and Glowacki introduced a classification system based on the pathophysiology of these lesions, and many of the confusion surrounding these lesions was clarified. The cell characteristics of 49 specimens from various vascular lesions were analyzed. This study found two major categories of lesions: hemangiomas and vascular malformations. This standard was adopted by the International Society for the Study of Vascular Anomalies (ISSVA) and continues to be accepted by many clinicians in current practice. Subsequent modifications to this classification system have included the addition of other rare vascular tumors distinct from hemangiomas, including Kaposiform hemangioendothelioma, tufted angioma, angiosarcoma, and others. With these additions, vascular anomalies continue to be divided into two categories: vascular tumors (including hemangiomas) and vascular malformations. In 1993, an embryologic perspective to further aid was adopted by the Hamburg classification system in the classification of vascular malformations. Lesions are identified firstly based on the
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prevailing vascular structure involved- arterial, venous, lymphatic, or capillary, and also consider arteriovenous shunting and combined vascular defects. In 1996, in addition to the clinical appearance and disease course, a classification system was developed by ISSVA based on histopathological and blood flow characteristics. According to this classification system, vascular anomalies are divided into two main categories: proliferating vascular tumors (hemangiomas) and vascular malformations. Vascular malformations, caused by inborn errors in vascular morphogenesis, are further classified according to the main type of vessel they are composed of: capillary, venous, lymphatic, arterial, and combined malformations. Vascular malformations are further subdivided into low and high blood flow groups and complex combined groups. In 2014, ISSVA updated classification of vascular anomalies. The general biological scheme of the classification is retained. The section on tumors has been expanded and main recognized vascular tumors are listed, which are classified as benign, locally aggressive or borderline, and malignant. A list of well-defined diseases is included under each generic heading in the “Simple Vascular Malformations” section. A short definition is added for eponyms. Two new sections were created: one dealing with the malformations of individually named vessels (previously referred to as “truncular” malformations); the second group lesions of uncertain or debated nature (tumor versus malformation). This classification is meant to be a framework, acknowledging that it will require modification as new scientific information becomes available. These classification systems have helped clarify the distinctions between different vascular anomalies, leading to improved management and better treatment options. Lymphangioma is a rare and benign disease presenting as a congenital lymphatic malformation that arises because of a defect in bud development. Histologically, lymphangioma is subdivided into three types according to the size of the lymphatic channels they contain—i.e., cystic (macrocystic), capillary (super-microcystic), and cavernous (microcystic). Cystic lymphangiomas are the most common, and the cavernous type is relatively rare. Lymphangioma development generally depends on the tissue density of the surrounding structure. Some patients present with symptoms such as dysphagia, dyspnea, cough, or chest pain when problems related to compression of vital structures develop. Cystic lymphangiomas most commonly appear around fat tissue where there is little resistance to their growth; they include cervical, mediastinal, and axial lesions. On the other hand, cavernous or capillary lymphangiomas often appear around muscular tissues of lip, cheek, or tongue, where the resistance of the surrounding tissue is greater. Surgical resection is recommended as the diagnostic and therapeutic modality.
8 Mediastinal Soft Tissue Tumor
8.1.11 Case 11 A 59-year-old woman complained of chest pain and tightness for half a month. Examination revealed a soft mass on the right thyroid. Contrast-enhanced chest CT showed right chest mass and pleural effusion. A puncture on the anterior wall of the right chest showed bloody pleural effusion. B-ultrasound in the right neck showed a low echo thyroid nodule, considering the possibility of a venous tumor. The mass in the right neck was significantly enlarged (reversible) when coughing. Chest B-ultrasound considered polycystic lesions with fluid inside. Chest CT: The mass was closely related to the middle mediastinum, surrounding superior vena cava, right innominate vein, and right pulmonary artery. The CT attention was 30HU (Fig. 8.32). [Diagnosis] Mediastinal lymphangioma [Diagnostic basis] Chest CT showed a giant cystic lesion with a clear boundary, protruding to the right upper lung, surrounding the superior vena cava, and causing its stenosis, the adjacent structures were significantly compressed and
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displaced. No obvious enhancement was found, and the CT attention was 30HU, indicating the density of water sample. The soft tissue mass in the neck varies its size with pressure, suggesting that the mass may be connected to the root of the neck, which supports the diagnosis of lymphangioma. Intraoperatively, the cyst wall of the lymphatic vessel was seen, and the pathology was confirmed to be lymphangioma. [Analysis] Lymphangioma is a congenital malformation of the lymphatic system including focal proliferations of well-differentiated lymphatic tissues that present as multicystic or sponge-like accumulations. Failing to communicate with peripheral drainage pathways, sequestered primitive lymphatic tissue produces lymphangioma. Secondary forms develop in adults due to lymphatic channel obstruction caused by surgery, radiation, or infection. In 2014 classification of ISSVA, the vascular malformations are divided into four groups: simple vascular malformations, combined vascular malformations, malformations of major named vessels, and malformations associated with other anomalies. Simple vascular malformations consist of
Fig. 8.32 Chest CT images of a 59-year-old woman complained of chest pain and tightness for half a month
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only one kind of vessel (capillaries, lymphatic vessels, or veins), except for arteriovenous malformations, which include arteries, veins, and capillaries. Common (cystic) lymphatic malformations represent a category in the spectrum of simple vascular malformations. Cystic lymphatic malformations result from sequestered lymphatic sacs that failed to fuse with peripheral draining channels. Lymphatic malformations are classified into 3 morphologic types: macrocystic (diameter >1 cm), microcystic (diameter 10/10 HPF). Epithelioid MPNSTs are generally highly cellular, may have focal or geographic necrosis, and can exhibit tumor cell spindling. Epithelioid MPNSTs differ from conventional malignant peripheral nerve sheath tumor by showing diffuse S100 protein and SOX10 positivity, infrequent association with NF1, and occasional origin in a schwannoma. Approximately 40% of them show diffuse loss of INI-1. GFAP and keratin expression is variable. The differential diagnosis of epithelioid MPNST includes clear cell sarcoma, melanoma, epithelioid sarcoma, and carcinoma. Lack of expression of melanocytic markers (e.g., Melan-A, MITF, and HMB45) is very helpful in distinguishing epithelioid MPNST from clear cell sarcoma and melanoma, and absence of cytokeratin expression distinguishes them from epithelioid sarcoma and carcinoma. A loss of SMARCB1/INI1/BAF47 protein expression may be shown in both epithelioid MPNST and epithelioid sarcoma, a potential diagnostic pitfall in the differential diagnosis with malignant rhabdoid tumor. Myoepithelial carcinoma may be a consideration given epithelioid morphology, myxoid
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Fig. 9.56 A 61-year-old woman with irregular soft-tissue mass in the right posterior superior mediastinum. Chest CT showed enlarged intervertebral foramen (red arrow), adjacent bone compression (white arrow), necrosis and cystic change (yellow arrow), and peripheral
enhancement (Fig. 9.56a–d). MRI showed isointense on T1 (Fig. 9.56e) and hyperintense on T2 (Fig. 9.56f). Pathology was low-grade malignant peripheral schwannoma
b ackground, GFAP, S100 protein, and keratin positivity, and the potential for INI-1 loss. Myoepithelial tumors tend to be less diffusely S100 positive and, outside of the salivary gland, are rarely SOX10 positive. In this histologic and immunophenotypic setting, the finding of EWSR1 rearrange-
ment is highly specific for myoepithelial carcinoma but not sensitive. The majority of patients diagnosed with epithelioid MPNSTs are cured by their first surgery. Jo et al. [5] identified sixty-three cases in consultation files. There were
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Fig. 9.57 Chest CT images of a 17-year-old woman complained of cough repeatedly for 3 months
nine recurrences resulting in two deaths from local disease and five metastases resulting in two deaths. There is a comparatively low risk for recurrence and metastasis, irrespective of tumor depth.
9.7.12 Case 12 A 45-year-old man complained of cough and suffocation for 2 months.
Chest CT: There was a huge mass in the anterior superior mediastinum, and a few spot calcifications could be seen in the front of the lesion. The CT attentions of unenhanced scan, arterial phase, and venous phase were 24HU, 46HU, and 65HU, respectively (Fig. 9.58). [Diagnosis] Anterior mediastinum malignant tumor [Diagnosis basis] Intraoperatively, the mass measured 26 cm × 20 cm × 18 cm located in the anterior mediastinum, up to the base of the neck, down to the pericardium, extending to both sides of the chest cavity, infiltrating the left bra-
9 Neurogenic Tumors
Fig. 9.58 Chest CT images of a 45-year-old man complained of cough and suffocation for 2 months
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chiocephalic vein, left subclavian artery, diaphragm nerve, left vagus nerve, aortic arch and left pericardial layer, there was also sheet infiltration in front of the left hilum. Histologically, the tumor was mainly composed of spindle cells, some cells are epithelial (Fig. 9.59), some cells are long spindle, arranged in whorls (Fig. 9.60), and cartilage (Fig. 9.61) and glandular (Fig. 9.62) differentiation can be seen in the tumor. Immunohistochemistry demonstrated positivity for CD99, Bcl-2, and CK8/18, and negativity for S100, MBP, NF, EMA, GFAP, CD34, and Desmin. Pathological diagnosis was malignant peripheral nerve sheath tumor with chondrosarcoma-like differentiation and glandular differentiation, invading the pericardial wall.
Fig. 9.61 Cartilage differentiation can be seen in the tumor
Fig. 9.59 The tumor was mainly composed of spindle cells, and some cells were epithelial
Fig. 9.62 Glandular differentiation can be seen in the tumor
Fig. 9.60 The tumor was mainly composed of spindle cells, arranged in whorls
[Analysis] Although neurogenic tumors located in the anterior and middle mediastinum only account for 10% of the total, the incidence of malignancy is much higher than that of the posterior mediastinum. Remarkable developmental plasticity, including divergent differentiation, may be shown in MPNSTs. Although not entirely specific, frequent histologic findings include fascicles of alternating cellularity, palisades, whorls, or rosette- like arrangements, perineural/intraneural spread when associated with nerve, subendothelial accentuation of tumor cells, and large areas of geographic like necrosis. Heterologous differentiation in the form of cartilage and bone, or less commonly smooth muscle, skeletal muscle (so- called malignant triton tumor), angiosarcoma, and even well- formed glands occur on occasion, particularly in patients with NF1.
9 Neurogenic Tumors
According to the 2007 WHO classification criteria for nervous system tumors, malignant schwannoma was divided into Epithelioid MPNST, MPNST with glandular differentiation, and MPNST with mesenchymal differentiation (also known as malignant tritontumor, MPNST with rhabdomyosarcoma differentiation). The 2016 version of the new classification added a subtype of perineurial MPNST. Special histological structures such as MPNST with glandular differentiation and MPNST with mesenchymal differentiation were classified into the subtype of MPNST with divergent differentiation. The pathology of this case is in accordance with the new classification of MPNST with divergent differentiation. MPNST needs to be distinguished from synovial sarcoma, particularly its monophasic variant. Synovial sarcomas usually involve nerves and may even grow in a multinodular or plexiform growth pattern. Although glandular differentiation may be shown in both synovial sarcoma and MPNST, glandular MPNST tends to show glands similar to enteric epithelium with frequent endocrine differentiation, whereas those of synovial sarcoma are lined by cuboidal cells. It is often accompanied by intraluminal eosinophilic necrotic debris. Obviously, a history of NF1 and/or a coexisting neurofibroma precursor indicate the diagnosis of MPNST. By immunohistochemistry, low molecular weight cytokeratins and EMA may be expressed in both synovial sarcoma and MPNST, although the expression of high molecular weight cytokeratins is seen only in synovial sarcoma. S100 may express in both tumors, but CD34 express only in MPNST. Although typically diffuse and strong in synovial sarcomas, transducin-like enhancer protein (TLE1) expression may also be present in a somewhat weaker, more variable pattern in some MPNST. Given the limited discriminatory power of histology and immunophenotype in the dif-
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ferential diagnosis of MPNST and synovial sarcoma, a definitive diagnosis of intraneural synovial sarcoma may require demonstration of SS18-SSX1 or SS18-SSX2 gene fusions, usually resulting from a characteristic t(X;18) translocation, because these gene fusions are limited to synovial sarcoma.
9.7.13 Case 13 A 20-year-old woman found a mediastinum mass. Chest CT: Contrast-enhanced CT image showed a heterogeneous mass in the right posterior mediastinum with regular contour and a slight degree of enhancement (Fig. 9.63). [Diagnosis] Neurofibroma [Diagnosis basis] The posterior mediastinal paraspinal lesion exhibits dilated growth rather than invasive growth. Visible compression of the thoracic spine and ribs can be seen, considering benign neurogenic tumors. Intraoperatively, the tumor was solid and yellowish. Microscopically, it contained cells with long, narrow nuclei as well as wavy bands of spindle-shaped cells with myxomatous interstitial tissue in the background. The histopathological diagnosis was neurofibroma. [Analysis] Neurofibroma was first reported by Verocay in 1908. The disease can occur at any age and there is no obvious gender difference. CT shows sharply marginated, smooth, or lobulated mass with possible split fat sign. Osseous pressure erosion of adjacent ribs and calcification may be seen. CT scan is low density, the CT attention is 20–25HU, mainly due to lipid-rich nerve sheath cells, adipocytes and mucoid degeneration, the central necrosis and cystic change of large tumors are another reason for low density. On MRI, homogeneous low to intermediate signal
Fig. 9.63 Chest CT images of a 20-year-old woman found a mediastinum mass
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intensity on T1-weighted images were shown in neurofibroma. On T2-weighted images, the peripheral region sometimes appears higher signal intensity than the central region (target sign). Corresponding to myxoid degeneration, there are high-intensity regions in the periphery of a neurofibroma on T2-weighted images, whereas nodular areas of low signal intensity correspond to collagenous fibrous tissue. The pattern was absent in lesions with cystic, hemorrhagic, or necrotic degeneration. Varma et al. [6] reported that this target sign on T2-weighted MR images was seen in 52% of cases, and proved helpful in differentiating neurofibroma from malignant peripheral nerve sheath tumors. A target pattern was not visible in malignant lesions. MRI cannot distinguish schwannoma from neurofibroma, and benign tumor may mimic malignant nerve sheath tumors when cystic, hemorrhagic, and necrotic degeneration is present.
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9.7.14 Case 14 A 76-year-old man complained of chest pain for 1 month. Chest CT: A dumbbell-shaped soft tissue mass could be seen on the right chest wall intercostal space, the density was lower than the muscle, and contrast-enhanced CT image showed a slight degree of enhancement during the venous phase (Fig. 9.64). [Diagnosis] Neurofibroma [Diagnosis basis] The lesion grows in a dumbbell shape across the intercostal space, and the adjacent rib is compressed. The diagnosis first considers schwannomas or neurofibromas. The density of the lesion is uniform, no enhancement in the arterial phase, and mild enhancement in the venous phase, which is more in line with the characteristics of neurofibroma. Pathology showed fusiform tumor cells, bland nuclei with inky chromatin, no mitosis, and loose
Fig. 9.64 Chest CT images of a 76-year-old man complained of chest pain for 1 month
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interstitial. Immunohistochemistry showed S100 positive, and Calretin and CD68 negative. The diagnosis considers neurofibroma. [Analysis] Neurofibroma consists of a proliferation of thick wavy collagen bundles with varying degrees of myxoid degeneration. Neurofibroma also incorporates a mixture of nonneoplastic peripheral nerve components, including axons, fibroblasts, perineurial cells, and variable inflammatory elements, such as mast cells and lymphocytes. By immunohistochemistry, all forms of neurofibroma are positive for S100, SOX10, and CD34. CD34 often has a characteristic “thumbprint” pattern. In contrast to neurofibroma in other localizations, mediastinal neurofibroma is pseudoencapsulated. Pseudoencapsulation was considered to be a host reaction toward the tumor and not a well-defined fibrous capsule. Some neurofibromas exhibit unusual features such as degenerative cytological atypia (atypical neurofibroma, neurofibroma with ancient change) and/or increased cellularity (cellular neurofibroma), often resulting in the differential diagnosis with MPNST. Immunohistochemistry and genetics play no role in these distinctions. Neurofibromas with atypical features harbor genetic changes that are seen in MPNSTs but not typical neurofibromas, namely loss of CDKN2A/ p16, p53, SMARCA2, and others, especially on the 9p2 locus. The term “atypical neurofibroma” should be avoided as it confuses ordinary neurofibromas with degenerative atypia and neurofibromas with true atypical features and premalignant genetic changes. Neurofibromas with atypical features usually develop within a plexiform neurofibroma, which are typically located along major nerves and are not amenable to resection without substantial morbidity. Therefore, despite the increased risk of MPNST in NF1 patients, care should be taken not to over-diagnose malignancy or atypia. Schwannomas are encapsulated lesions derived from nerve sheaths, which grow from the formation of a lateral mass on the parent nerve, often making the nerve easier to recognize. Schwannomas do not involve the nerve fibers themselves, so they can be resected without sacrificing the nerve, if necessary. On the contrary, it is often impossible to completely resect the neurofibroma while preserving the original nerve, because neurofibromas are nonencapsulated tumors comprising all nerve elements, i.e., axons, sheath cells, and connective tissues.
9.7.15 Case 15 A 17-year-old man complained of right chest pain for 3 months. Chest CT: There were multiple soft tissue lesions on the right anterior chest wall, right posterior spinal wall, and
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mediastinum, and the contrast-enhanced scan showed mild and delayed enhancement in the center of the lesions. Low- density lesions were seen behind the bilateral psoas major muscle and there were multiple soft subcutaneous small tumors (Fig. 9.65). [Diagnosis] Neurofibromatosis [Diagnosis basis] A young man with low-density lesions in chest wall, mediastinum, bilateral posterior psoas major muscle, and subcutaneous tissue, the diagnosis first considers neurofibromatosis. The patient underwent biopsy. Microscopically, the tumor was composed of spindle-shaped cells with narrow nuclei without atypia. Edematous interstitial tissue was seen in the background. The histopathological diagnosis was neurofibroma. [Analysis] Neurofibromatosis is a heterogeneous group of hereditary cancer syndromes that result in tumors of the central and peripheral nervous systems. By far neurofibromatosis type 1 (NF1, 96%) is the most common form, followed by neurofibromatosis type 2 (NF2, 3%), and the lesser-known form of schwannomatosis. There is no gender or racial predilection in neurofibromatosis. NF2 is an autosomal dominant disorder caused by mutations to the NF2 tumor suppressor gene on chromosome 22q12.2, characterized by a variety of nonmalignant nervous system tumors, including schwannomas, ependymomas, meningiomas, and gliomas, with vestibular schwannomas being the hallmark lesion, affecting 95% of individuals and typically appearing bilaterally. Ocular and cutaneous manifestations also occur. As the name implies, schwannomatosis is a syndrome characterized by the development of multiple peripheral nerve schwannomas, without concomitant involvement of the vestibular nerve. Schwannomatosis is caused by a mutation in the SMARCB1gene, also known as the INI1, BAF47, or hSNF5 gene, located on chromosome 22q11.2, centromeric to the NF2 gene. Unlike NF1 patients with characteristic dermatological findings and NF2 patients with eighth cranial nerve dysfunction at a young age, patients with schwannomatosis have nonspecific symptoms that may delay presentation or imaging time. The majority of the cases of schwannomatosis are caused by de novo mutations, though familial cases exist with an autosomal dominant inheritance pattern. Even in the familial forms, a germline SMARCB1 mutation is only identified in 40– 50% of cases, indicating that other genetic loci yet to be identified are involved. The hallmark peripheral nerve sheath tumor in NF1 is neurofibroma. Neurofibromas can be deep, involving single or multiple nerves. These are termed plexiform neurofibromas. There are also cutaneous neurofibromas that involve the skin thickness and cases in which neurofibromas are diffuse and involve both the skin thickness and the deep nerves. Plexiform neurofibromas are estimated to occur in up to 50%
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Fig. 9.65 Chest CT images of a 17-year-old man complained of right chest pain for 3 months
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of people with NF1. Cutaneous neurofibromas impact up to 99% of adults with NF1. More rarely, there are atypical neurofibromas and malignant peripheral nerve sheath tumors. Multiple neurofibromas and plexiform neurofibromas should prompt consideration of NF1. Plexiform neurofibromas are characteristic of NF1 and extend along one or multiple nerves and their branches. Most commonly seen in the paraspinal regions, they may also affect the brachial plexus or extremities. The identification of positive family history for NF1, intercostal neurofibromas, café-au-lait spots, or some combination of those factors would help the diagnosis of plexiform neurofibromatosis of the chest. A plexiform neurofibroma by definition involves multiple fascicles of a nerve and is composed of a proliferation of cells extending along the length of the nerve. Usually poorly circumscribed and locally invasive, these tumors contain a heterogeneous mix of Schwann cells, fibroblasts, and other cell types. The nerve is thickened and frequently some surrounding soft- tissue hypertrophy is seen. Although plexiform neurofibromas are considered benign, there is a risk of malignancy in approximately 2–5% of cases. Plexiform neurofibromas usually appear as smooth, well-delimited, round, or elliptical masses in the paravertebral region or along the path of the vagus, recurrent laryngeal, phrenic, or intercostal nerve. Plexiform neurofibromas are usually extensive fusiform or infiltrating masses that tend to surround mediastinal vessels with loss of normally visible fat planes and can cause diffuse mediastinal widening. They show variable contrast material enhancement and may calcify. Both types can remodel, erode, invade, or even destroy adjacent bone structures, thereby simulating more aggressive lesions. It is important to note that these lesions can exert pressure to mediastinal structures, such as the trachea, esophagus, blood vessels, or nerves. The symptoms are mainly those of compression, with chest pain and cough being the most frequent. In rare cases, digestive and other respiratory symptoms, or even superior vena cava syndrome, can also be present. The clinical, imaging, and pathological characteristics of the case are consistent with plexiform neurofibroma. NF1 recommends various examinations, such as X-ray examination of the chest and long bones, CT scan of the brain and orbit, and MRI of the brain and orbit. Gliomas have a typical fusiform appearance with kinking in MRI. Genetic testing can be helpful when prenatal or preimplantation diagnosis is desired.
9.7.16 Case 16 A 52-year-old man complained of abdominal pain for 4 days. He and his father have a history of neurofibromatosis.
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Chest CT: Multiple nodules and masses in both lungs and a large number of pedunculated tumors on the skin surface (Fig. 9.66). [Diagnosis] NF1 [Diagnosis basis] A middle-aged male with multiple nodules and masses in both lungs, multiple pedunculated tumors on the skin surface (Fig. 9.67), and a family history of neurofibromatosis, all of them are consistent with the diagnosis of NF1. The patient underwent a needle biopsy, most of which were degeneration and necrotic fibrous connective tissue under the microscope, with small focal neurofibrous tissue and active growth. The pathological diagnosis was neurofibroma. [Analysis] Also known as von Recklinghausen disease or peripheral neurofibromatosis NF1 is an autosomal dominant tumor predisposition syndrome that is most easily characterized by the development of multiple neurofibromas of the peripheral nerves. Malignancies associated with NF1 include malignant PNSTs, leukemia, pheochromocytomas, gastrointestinal stromal tumors, and others. The incidence of NF1 is approximately 1 in every 2500–3000 births. Though about 50% have new mutations, inheritance is autosomal dominant with irregular penetrance and variable expressivity with the gene locus on 17q11. Each child of a parent with NF1 has a 50% risk of developing the disorder. It has a high rate of penetrance and the mutation rate of the NF gene is high with 80% being of paternal origin. The NF1 gene protein product, neurofibromin, is a tumor suppressor expressed mainly in neurons, Schwann cells, glial cells, and melanocytes. A central region of neurofibromin is structurally and functionally homologous to GTPase-activating proteins, which promote the hydrolysis of p21Ras-GTP (the active form) to p21Ras- GDP (the inactive form) by stimulating intrinsic p21Ras- GTPase activity. Because p21Ras proteins play central roles in cell differentiation and growth, inactivation of the NF1 gene is conducive to the active state (p21Ras-GTP), leading to the permanent stimulation of a cascade of signals and excessive cell division owing to nonregulated activation of the MAP kinase pathway. This pathway could play a role in the development of benign neurofibroma-type tumors, malignant PNSTs, pulmonary hypertension with hyperplasia of pulmonary artery smooth-muscle cells, and interstitial disease, such as hyperplasia/metaplasia of interstitial pulmonary fibroblastic cells. The earliest known depiction of speculated neurofibromatosis dates back to the thirteenth century with sketches by a Cistercian monk. In 1862, Virchow mentioned the hereditary component when he described a man in which the “body was quite covered with lumps from pinhead-sized to pigeon egg- sized” and he pointed out that the “peculiarities have existed in an inherited manner already over three generations.” However, in 1882, Friedrich von Recklinghausen, a student
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Fig. 9.66 Chest CT images of a 52-year-old man complained of abdominal pain for 4 days
Fig. 9.67 A patient has heterogeneously morphologic appearance of cutaneous neurofibromas, including sessile, globular, and pedunculated cutaneous neurofibromas
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of Virchow, gave the most comprehensive clinical and histological description of the disease and coined the term “neurofibroma.” Diagnostic criteria of NF1 was developed in 1987 through the National Institutes of Health Consensus Conference and was updated in 1997. A clinical diagnosis of NF1 requires the presence of at least two of the following features: six or more café au lait macules (diameter >5 mm before puberty and >15 mm after puberty), two or more neurofibromas or one plexiform neurofibroma, freckling in the axillary or inguinal regions, optic pathway glioma, two or more Lisch nodules in the irides, a distinctive bony lesion such as sphenoid dysplasia or thinning of the long bone cortex, and a first-degree relative with NF1. Approximately 50% of patients meet the diagnostic criteria for NF-1 before the age of 1 year, 97% meet the criteria up to the age of 8 years, and virtually all patients fulfill them by the age of 20 years. Café-au-laitmacules (CALM) are flat, hyperpigmented skin lesions that appear during infancy, and are one of the diagnostic features of NF1 (Fig. 9.68). By adulthood, about 95% of patients with NF-1 have CALM. While not completely specific for NF1, the number of CALMs at presentation is a strong predictor for the diagnosis of NF1. Therefore, greater than five CALMs in a young child highly indicate NF1. However, in the absence of a positive family history of NF1, the presence of CALMs alone is not sufficient to establish a
diagnosis of NF1, and additional features are needed. Seventy percent of patients with NF-1 have freckling in the intertriginous areas of the axilla and in the inguinal region, which also can be found at the base of the upper neck, upper eyelids, and under the breasts. These freckles typically appear later in childhood and are usually used as the second diagnostic criterion. Often seen in 95–100% of adults with NF1, lisch nodules are hyperpigmented hamartomas of the iris (visualized best on slit-lamp examination). Lisch nodules usually do not cause any complication and appear as multiple pale, yellowishbrown, oval to round, and dome-shaped papules projecting from the surface of the iris. Neurofibromas may develop in many sites, and can appear as dermal, spinal, or plexiform neurofibroma subtypes. Arising in the nerves of skin, dermal neurofibromas are discrete masses and increase in number with advancing age. NF1 individuals have variable numbers of dermal neurofibromas, with some developing few and others harboring thousands of neurofibromas. Involving multiple nerve bundles, plexiform neurofibromas are complex benign nerve sheath tumors. Different from their discrete counterparts, these tumors are often congenital and grow most rapidly during the first decade of life. These tumors can appear anywhere throughout the body and may have symptoms that reflect nerve or soft-tissue compression. If the skin is overlying a plexiform neurofibroma, hyperpigmentation and fine hair growth may be exhibited in the tumor (Fig. 9.69).
Fig. 9.68 Café-au-lait macules in a region of axillary freckling with cutaneous neurofibromas
Fig. 9.69 Hyperpigmentation and hair growth
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Plexiform neurofibromas are detected on clinical examination in approximately 27% of individuals with NF1. Optic pathway gliomas, seen in about 15–20% of patients with NF1, are usually low-grade astrocytomas that can grow in the optic nerve, optic chiasm, optic tract, and hypothalamus. Almost all individuals with NF1 develop PNSTs, mainly benign neurofibromas, but about 10% of PNSTs will undergo transformation to malignant MPNSTs. Traditionally, surgical treatment of PNSTs has been considered as a standard approach. The indications for surgical resection of NF include neurologic impairment, pain, and severe disfigurement, and the purpose is to restore or protect function. However, surgery is often challenging or not feasible due to involvement of nervous system structures. The potential benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiation therapy was underscored by latest evidence and clinical implications for new therapies of PNSTs in patients with NF1.
9.7.17 Case 17 A 60-year-old man complained of pain in bilateral lower limbs for more than a month. On examination, the power of bilateral lower limbs was 4/5, and knee and ankle reflexes were brisk with extensor plantar response. MRI of the spinal cord revealed abnormal epidural signal behind theS1 level and multiple abnormal signals in the thoracic, lumbar, and back skin, and left erector spinae muscles at the L4–5 level. Chest CT: Multiple nodules and cystic changes in lungs, and left pleural effusion, and large number of pedunculated tumors on the skin surface (Fig. 9.70). [Diagnosis] NF1 [Diagnosis basis] The patient’s symptoms, signs, and imaging findings are consistent with NF1. [Analysis] NF1 is a genetic syndrome characterized by clinical manifestations of systemic and progressive involvement that mainly affect the nervous system, skin, bones, and eyes, and can affect any other organ. Collections of neurofibromas, café-au-lait macules, axillary and inguinal freckling, and pigmented hamartomas in the iris (Lisch nodules) are the main features of NF1 and represent some of the diagnostic criteria for this disease. Less common features include bone deformities (pseudarthrosis, dysplasia), short stature, scoliosis, seizure disorders, cognitive deficits, peripheral neuropathies, and more serious manifestations, such as plexiform neurofibromas, malignant PNSTs, and optic nerve and other central nervous system gliomas. Cognitive problems are the most common neurological complications in individuals with NF1. Severe intellectual disability with an intellectual quotient 8 cm in diameter originating from the retrospective cavity tend to metastasize to other distant organs.
9.7.22 Case 22 A 6-year-old boy’s physical examination revealed a left chest mass. Chest CT: A huge spherical mass in the left mediastinum with calcifications (Fig. 9.81). [Diagnosis] Neuroblastoma [Diagnosis basis] In children, the lesions are huge, and calcification is obvious. Neuroblastoma is considered and confirmed by pathology. [Analysis] Arising from neural crest cells, neuroblastoma is a solid tumor, which mature and develop into other cell types such as melanocytes, cranial neurons and glia, bone, cartilage, connective tissue as well as peripheral sympathetic neurons and Schwann cells. Neuroblastoma was originally described by Virchow in 1863; early reports considered the tumor as a glioma of the adrenal gland. By the beginning of the twentieth century, Zückerkandl and Kohn determined its origin in sym-
Fig. 9.81 Chest CT images of a 6-year-old boy’s physical examination revealed a left chest mass
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pathetic tissue. The surprising discovery that neuroblastoma could mature to ganglioneuroma was made in 1927. Many genomic studies have proved that single nucleotide polymorphisms (SNPs) in DUSP12 and HSD17B12 locus at chromosome 5q11.2 are connected with low-risk neuroblastoma, whereas SNPs within or upstream of CASC15 and CASC14 on chromosome 6p22, BARD1, LMO1, HACE1, and LIN28B as well as a common copy number variation at 1q21 within NBPF23 have been associated with high-risk disease. Furthermore, a significant association of African genomic ancestry with high-risk neuroblastoma supported genetic etiology for the racial disparities in survival observed in neuroblastoma. Additional sequencing studies are needed to find new risk variants and develop deeper understanding of the genetic etiology of neuroblastoma. Patients with neuroblastoma may present with symptoms affecting a variety of organ systems: respiratory (distress, infection, pneumonia), neurologic (Horner’s syndrome, ataxia, myoclonic jerk), or urogenital (urinary tract infections). The most often symptom is pain, caused by either local effects from the primary tumor or metastatic disease. Up to 2/3 of patients have metastatic bone disease at presentation. The next most frequent complaint is abdominal distention. Other presenting symptoms include irritability, malaise, weight loss, shortness of breath (from a large abdominal tumor), and peripheral neurologic deficit (from neural foraminal invasion and nerve compression by tumor). Less common presentations include Horner syndrome (pupillary constriction, ptosis, and ipsilateral facial anhidrosis and flushing from a mediastinal tumor) and opsoclonus- myoclonus. Opsoclonus-myoclonus is jerking movements of the extremities and eyes, sometimes with cerebellar ataxia. The cause is unclear but it is seen in 2% of patients and is related to a thoracic primary tumor and a better prognosis. Neuroblastic tumors are remarkable for their varied tumoral biologic behavior. One of the hallmarks of neuroblastoma and ganglioneuroblastoma is their tendency to secrete catecholamines. Most of catecholamines secreted are
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vanillylmandelic acid (VMA) and homovanillic acid (HVA). The vast majority (90–95%) of neuroblastoma and ganglioneuroblastoma secrete catecholamines, although the symptoms of catecholamine excess are rarely caused. Generally, the better differentiated the tumor, the more mature the catecholamine. Secreted as a metabolite of dopamine, the level of HVA may be elevated in more mature neuroblastoma and ganglioneuroblastoma. In contrast, VMA is a less mature metabolite of epinephrine and norepinephrine. Some centers evaluate a VMA-to-HVA ratio as an indicator of maturity. Ratios of less than 1 are considered favorable; ratios greater than 1 indicate an immature tumor and therefore a worse prognosis. Vasoactive intestinal peptide (VIP) may also be secreted by the tumor and may cause hypokalemia, watery diarrhea, and acidosis. VIP is believed to be elaborated by ganglion cells within the tumor. VIP-producing tumors tend to be more mature, and have a better prognosis. The Children’s Oncology Group (COG) has traditionally used the following factors to stratify patient risk. (1) Age at diagnosis, (2) stage to define extent of disease by the International Neuroblastoma Staging System (INSS), (3) tumor histology using the International Neuroblastoma Pathology Classification (INPC) criteria, (4) MYCN status (amplified versus nonamplified), and (5) DNA index or tumor cell ploidy. Older age has been prognostic of poor outcome in neuroblastoma since the 1970s. Compared with older children, younger children, especially infants