Ken Y Yoneda, MD, Brian M Morrissey, MD, and David K Shelton, MD University of California, Davis School of Medicine, and Veterans Affairs Northern California Health Care System

Originally printed in:
» US Respiratory Care 2006 - December 2005

Reference Section B USINESS BRIEFING: US RESPIRATORY CARE 2006 1 a report by Ken Y Yoneda, MD, Brian M Morrissey, MD, and David K Shelton, MD University of California, Davis School of Medicine, and Veterans Affairs Northern California Health Care System Mediastinal tumors comprise a diverse group of benign and malignant processes, all sharing an anatomic region—the mediastinum, which occupies the medial thorax, excluding the lungs, hila, and pleura.

Traditionally, the mediastinum is divided into three compartments: anterior, middle, and posterior. This scheme, based on divisions viewed on the lateral chest radiograph (CXR), does not correlate with any true anatomic compartments. Rather, it is based on the tendency for a given group of tumors to be located in these radiographic locations (see Table 1).

Several other schemes exist, but the authors prefer the following: • anterior mediastinum—immediately posterior to the sternum and extending to the anterior cardiac and tracheal borders; • posterior mediastinum—posterior to a line 1cm dorsal to the anterior edge of the vertebral bodies;and • middle mediastinum—the remaining area between the two (see Figure 1).

With the diverse nature of these tumors and the often complex diagnostic and treatment strategies employed, the authors recommend a multi-disciplinary approach, enlisting the expertise of a pulmonologist, qualified radiologist, thoracic surgeon, medical oncologist, and radiation oncologist.

Imaging A CXR often initiates the evaluation of mediastinal disorders but is rarely diagnostic. Notable exceptions are, in the first instance, eggshell calcifications—strongly suggesting silicosis, treated lymphoma, or sarcoidosis— and, in the second instance, teeth or bones within a mass, which are diagnostic of a teratoma.Air fluid levels suggest an esophageal origin, hernia, cyst, or abscess. Except for a mass of suspected thyroid origin, evaluation should proceed to computed tomography (CT) of the chest.

CT helps delineate anatomic location, extent of disease, tissue invasion, and tissue density. Iodinated contrast should be administered unless contraindicated or thyroid origin is suspected. CT is occasionally diagnostic and is usually sufficient for pre-operative evaluation.It is useful in imaging associated mediastinal or hilar lymph nodes, distinguishing mediastinal tumors from vascular abnormalities, identifying concomitant parenchymal lung disease, and demonstrating complex or variant anatomy.2–4 Magnetic resonance imaging (MRI) is superior to CT for imaging nerve plexus and blood vessels, distinguishing tissue planes and invasion, and imaging in non-transaxial planes. MRI is particularly useful when iodinated contrast is contraindicated, for imaging posterior mediastinal masses and for assessing tissue, vascular, or cardiac invasion.5 Thyroid scanning with radioactive iodine can identify and evaluate masses of suspected thyroid origin.

Alternative thyroid imaging modalities are thalium-201 imaging, technetium-99m-sestamibi imaging,6 positron emission tomography with 18 fluorodeoxyglucose (FDG-PET),7 or scintigraphy with radiolabeled octreotide, a synthetic analog of somatostatin.8 Technetium-99m-sestamibi imaging is 90–100% sensitive for identifying parathyroid adenomas in the neck and mediastinum and may identify parathyroid carcinomas.9–10 11C-methionine PET may more accurately localize parathyroid adenomas.11 Radiolabeled octreotide is used for imaging thymic carcinoids, demonstrating both primary lesions and distant metastases.12 PET and the newer combined PET/CT fusion imaging demonstrate the metabolic activity of a tumor utilizing the glucose analog FDG or other tracers.The malignant nature of a tumor, whole body staging or re-staging, and response to therapy may be better assessed. For the mediastinum, it is most useful in thymomas, thymic carcinomas, germ cell neoplasms, lymphomas, and lung and esophageal carcinomas (see Figure 2).

Anterior Mediastinum Most anterior mediastinal masses and cysts, even when benign, require surgical resection. For many of these Mediastinal Tumors—A Diagnostic Approach Ken Y Yoneda, MD, is an Associate Professor of Clinical Internal Medicine in the Division of Pulmonary and Critical Care at the University of California, Davis School of Medicine. He is also the Assistant Chief of Pulmonary and Critical Care of the Veterans Affairs, Northern California Health Care System. He is the pulmonary representative for thoracic oncology at both of these institutions and has a sub-specialty interest in invasive pulmonary. Dr Yoneda’s major research interests are in lung cancer and tobacco-related disease and he is a scientific advisor to the California Lung Association and the California Tobacco Related Research Program.

Brian M Morrissey, MD, is an Assistant Professor in the Division of Pulmonary/Critical Care Medicine at the University of California, Davis School of Medicine. He directs the Adult Cystic Fibrosis Center and acts as Associate Director of the Pulmonary Fellowship Program.

David K Shelton, MD, is a Professor of Radiology and Nuclear Medicine at the University of California Davis Medical Center. His primary areas of interest are cardiothoracic imaging and functional imaging.

Oncological imaging for tumor identification, staging, and tumor response to therapy are specific research interests.

2 B USINESS BRIEFING: US RESPIRATORY CARE 2006 Reference Section lesions, delaying surgical consultation or attempting invasive diagnostic studies is unnecessary and potentially risky.14,15 Therefore, any suspicious lesion should, in general, be resected. Video-assisted thoracic surgery (VATS) is increasingly used to diagnose and treat mediastinal tumors.16–18 The decision to perform VATS, standard cervical mediastinoscopy, anterior mediastino- tomy, thoracoscopy, or thoracotomy is aided by CT findings and is predicated regarding the nature of the lesion, the intent to biopsy or resect, and the skill and experience of the surgeon.

Bronchoscopy with needle aspiration biopsy is useful for diagnosing subcarinal, hilar, and paratracheal masses and adenopathy.Ultrasound (U/S)-guided bronchoscopy may significantly improve the diagnostic accuracy of bronchoscopic needle aspiration.19 Endoscopic U/S- guided transesophageal biopsy is useful in sampling para- esophageal lymph nodes and is complementary to U/S- guided bronchoscopy.20,21 CT-guided percutaneous fine-needle aspiration (FNA) can access anterior mediastinal neoplasms.22 Definitive diagnosis of lymphoma requires relatively large tissue samples, and larger core-needle biopsies should be used.

Flow cytometry should be sent, but requires rapid processing of relatively large amounts of fresh tissue.All negative and non-diagnostic results should be followed up aggressively.23 If findings are equivocal or suspicious, then mediastinoscopy or parasternal mediastinotomy should be considered.

Lesions that deserve definitive histological confirmation before or without surgical resection include: • those that demonstrate tissue invasion, superior vena caval obstruction, pleural effusion, or metastasis; •lymphomas; • non-seminomatous malignant germ-cell tumors;and • seminomas.24,25 Thymoma Thymomas are the most common neoplasms of the anterior mediastinum. Patients may present with a cough, chest pain, dyspnea, dysphagia, hoarseness, superior vena caval syndrome, neck mass, or myasthenia gravis. Serum anti-acetylcholine receptor antibody levels should be measured.

Complete surgical resection is considered the treatment of choice for both malignant and benign thymomas; thus, pre-operative differentiation is unnecessary.14,26,27 However, demonstration of tissue invasion or an associated pleural effusion on CT is highly suggestive of an unresectable malignant thymoma. In such cases, a multidisciplinary approach is recommended.

Table 1: Mediastinal Tumors Benign Malignant Anterior Thymoma Thymic carcinoma Thymic cyst Thyroid carcinoma Thymolipoma Seminoma Thymic hyperplasia Mixed germ-cell Thyroid Lymphoma Cystic hygroma Thymic carcinoid Parathyroid adenoma Foramen of morgagni hernia Middle Benign adenopathy Lymphoma Cysts Metastases Esophageal mass Esophageal cancer Hiatal hernia Thyroid carcinoma Cardiac and vascular structures Lipomatosis Cardiophrenic fat pad Foramen of morgagni hernia Ectopic thyroid Posterior Neurofibroma Neuroblastoma Schwannoma Chemodectoma Foramen of bochdalek hernia Meningocele Cysts Figure 1: Divisions of the Mediastinum on a Lateral Chest Radiograph The anterior mediastinum is ventral to the line drawn down the anterior tracheal and cardiac borders.The posterior mediastinum is dorsal to the line drawn 1cm posterior to the anterior vertebral bodies.The middle mediastinum is located between the two.

Mediastinal Tumors—A Diagnostic Approach B USINESS BRIEFING: US RESPIRATORY CARE 2006 3 Germ-cell Tumors Teratomas Teratomas are the most common germ-cell tumors of the mediastinum. They commonly occur in the third and fourth decade of life, with a male predominance.28,29 When teeth or bone are seen within a mass on CXR, or when any combination of fat, fluid, soft tissue, and calcium densities are noted on CT, teratoma can be diagnosed with a high degree of confidence (see Figure 3). Although most teratomas are benign, all should be resected because of their mass effect and the 20% incidence of local invasion.24 Seminomas Malignant seminomas occur in men aged 20–40 years.

Beta-human chorionic gonadotropin (beta-hCG) is occasionally positive.30 Diagnosis can be established by needle biopsy, and should be pursued, as seminomas may be optimally treated with radiation and/or chemotherapy.

Surgical resection of residual disease may be required.

Non-seminomatous Germ-cell Tumors Primary mediastinal malignant non-seminomatous germ-cell tumors occur in young men and may be associated with Kleinfelter’s syndrome. Alpha- fetoprotein (AFP) serum and beta-hCG are elevated in the vast majority of cases.Although an elevated AFP is considered diagnostic, needle biopsy may otherwise be required.31 Generally, these tumors do not respond well to any therapy, but aggressive multidisciplinary treatment may still be warranted.

Lymphoma The mediastinum is commonly involved in disseminated lymphoma. However, both Hodgkin’s and non- Hodgkin’s lymphoma may present as a primary anterior mediastinal tumor. Hodgkin’s lymphoma responds well to chemotherapy and/or radiotherapy, while primary mediastinal non-Hodgkin’s lymphoma in general does not. Surgery has virtually no therapeutic role.

Thymic Carcinoid The course of thymic carcinoids is unpredictable, but tends to be aggressive. Serum serotonin, chromogranin-A (CgA) and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels may be elevated. Octreotide scanning is confirma- tory and may identify metastatic disease. Symptoms and tumor growth can be palliated with somatostatin analogs.

To prevent carcinoid crisis, prophylaxis prior to tumor manipulation should be considered. Radical resection is recommended where possible and adjuvant radiation and chemotherapy may be warranted.32–34 Middle Mediastinum Adenopathy The most common masses of the middle mediastinum are lymphatic. Lymphadenopathy may result from infection, Figure 2: Contrast-enhanced CT Image Versus a Fusion PET/CT Image Figure 3: An Anterior Mediastinal Mass The contrast-enhanced CT scan (left) shows a large mediastinal mass in a 43-year-old woman.The fusion PET/CT image demonstrates an FDG-avid middle mediastinal mass.The PET/CT fusion allows functional metabolic information to be fused with the more anatomical CT data. CT = computed tomography, FDG = fluorodeoxyglucose, PET = positron emission tomography.

A = calcifications (272 Hounsfield units), B = fat density (-35.5 Hounsfield units) consistent with a teratoma.

4 B USINESS BRIEFING: US RESPIRATORY CARE 2006 Reference Section inflammation,or a primary or metastatic neoplasm.When associated with a pulmonary mass or infiltrate, broncho- scopy with endobronchial or transbronchial biopsy is often diagnostic. Otherwise, histologic confirmation can be pursued as for the anterior mediastinum.

Bronchogenic Cysts Bronchogenic cysts are most commonly subcarinal in location.They are usually of uniform water or near- water density but occasionally demonstrate high- density fluid on CT. Bronchoscopic or CT-guided needle biopsy is diagnostic when clear fluid is obtained (see Figure 4). However, turbid or mucoid fluid may also be seen. A diagnostic MRI precludes the need for further work-up. Surgery is recommended when patients become symptomatic, but some authors recommend earlier resection.

Pericardial Cysts Pericardial cysts, typically asymptomatic, abut the heart and are identified on CT as well-defined, unilocular, non-enhancing masses of water density. They can be followed clinically and radiographically, and only require surgical resection if they are symptomatic or exhibit atypical radiographic features.35 Posterior Mediastinum Most posterior mediastinal masses are neurogenic.

Exceptions are lymphatic, esophageal, aortic, or cystic abnormalities, and, rarely, extramedullary hemato- poiesis.MRI is the imaging modality of choice,because of the predominance of neurogenic tumors.

The treatment of choice for neural tumors is surgical resection. In locally invasive sympathetic ganglia tumors, radiation therapy and adjuvant chemotherapy may be indicated. Malignant sympathetic ganglia tumors most frequently metastasize to the lungs; chemotherapy and radiation therapy without surgery are then recommended. Meningoceles may be followed clinically and radiographically. On CT and MRI, meningoceles appear as sharply demarcated cysts having continuity with the thecal sac.

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