Primary benign anterior and middle mediastinal tumors arise from mediastinal structures either as benign neoplastic processes or as a result of inflammation. They may also occur as a result of local extension of adjacent compartment organ growth into the neighboring space or as a result of the arrest of embryonic cells traversing this compartment with later tumor growth. Uncommon primary mediastinal tumors usually are of mesenchymal origin. These tumors represent fewer than 10% of primary mediastinal tumors and have a higher prevalence and malignant potential in children.1
Primary mediastinal tumors are divided for the convenience of diagnosis and surgical approach into three compartments: anterior, middle, and posterior. Each compartment is defined by theoretic anatomic borders (Fig. 161-1) and each is specific for certain tumors. These compartments are described as follows.
Anterior mediastinum: This compartment is bounded anteriorly by the sternum and posteriorly by the pericardium, the aorta, and the brachiocephalic vessels. The thoracic inlet comprises the superior border, and the inferior border is demarcated by the diaphragm. Tumors in the superior aspect of this compartment largely derive from tissues native to or passing through this compartment or extending down from the neck. Tumors in the inferior aspect consist primarily of hernias that extend superiorly from the abdomen or pericardial fat pad extensions or pericardial or mesothelial cysts.
Middle mediastinum: This compartment is bounded by the anterior and posterior reflections of the pericardium, and it stretches from the thoracic inlet to the diaphragm. It is probably best described as the space that lies between the anterior and posterior mediastinum.
Posterior mediastinum: This compartment is defined anteriorly by the posterior trachea and the pericardium and it extends to the vertebral column including the paraspinal areas with vertical dimensions from the apex of the thoracic cavity to the diaphragm.
This chapter focuses on benign anterior and middle mediastinal tumors and the common surgical methods used to deal with these tumors. It should be noted that histologic overlap may occur between benign and malignant tumors arising from similar tissues in the same compartment as noted in Table 161-1. In addition, it may be clinically and pathologically difficult to distinguish a benign from a malignant mediastinal mass (even if cystic) until the specimen has been removed and fully examined pathologically.
|BENIGN TUMORS||BENIGN WITH POSSIBLE MALIGNANT ASSOCIATION||MALIGNANT TUMORS|
|Thymic cysts||Thymic cyst associated with thymoma||Thymoma|
|Thymolipoma||Thymic neuroendocrine tumor|
|Germ cell origin|
|Teratoma||Cystic teratoma with malignant elements||Malignant germ cell tumor|
|Immature teratoma (<15 yrs)||Seminoma|
|Mature teratoma with <50% immature elements||Nonseminomatous germ cell tumor|
|Teratoma with malignant transformation|
|Bronchogenic cysts||Malignant bronchogenic cysts|
|Esophageal duplication cysts||Malignant esophageal duplication cysts|
|Endocrine cell origin|
|Mediastinal thyroid goiter||Mediastinal thyroid cancer|
|Parathyroid adenoma||Mediastinal parathyroid cancer|
|Parathyroid mediastinal cyst|
|Chemodectoma (nonsecreting)||Malignant paraganglioma|
|Benign nerve sheath tumors||Malignant nerve sheath tumors|
|Schwannoma (Neurilemmoma)||Malignant schwannomas|
|Sympathetic nerve origin|
|Congenital vascular anomalies|
|Lymphoma||Metastatic nodal disease|
|Lymphangioma (cystic hygroma in children)||Lymphangiosarcoma|
|Solitary fibrous tumor||Malignant solitary fibrous tumor|
|Malignant fibrous histiocytoma|
The differentiation on clinical grounds between benign and malignant mediastinal tumors is dependent on three major factors: mediastinal location, patient age, and the presence or absence of symptoms.2,3 Younger patients are more likely to suffer from neurogenic tumors (the majority are benign), lymphomas, or germ cell tumors (the majority are benign teratomas) compared with older patients, who tend to have anterior mediastinal tumors, which are more often malignant.4–8 Benign tumors are commonly asymptomatic; thus they often are discovered as incidental findings accompanying parallel investigations for other health problems. Malignant tumors are commonly symptomatic,3,5 possibly related to tumor size, complications of local compression, or systemic symptoms. Malignant mediastinal tumor product expression (e.g., adrenocorticotropic hormone, β-human chorionic gonadotropin, α-fetoprotein, calcium, parathyroid hormone, and acetylcholine receptor antibody levels) or the systemic consequences of these tumors (e.g., myasthenia gravis, pure red blood cell anemia, and agammaglobulinemia), may be indicative of the malignant potential in a mediastinal mass.
The pragmatic value of preoperative confirmation of benign from malignant mediastinal disease impacts not only survival and tumor recurrence but also allows for greater freedom with respect to surgical approaches. Surgical standards mandate the use of larger incisions for malignant mediastinal tumors to allow for tumor removal without local dissemination and to account for factors of size, diffuse adherence, hypervascularity, and local invasion to adjacent structures.9 However, this is not the case for benign tumors, where with respect to surgical approach the only constraints are complete tumor removal, patient safety, and procedural morbidity.
Radiographic presentations of these tumors are often nonspecific and may be difficult to distinguish from malignant tumors as outlined in Table 161-2.10 However, serum tumor markers, contrast enhancement, and ultrasound or CT-guided mediastinal biopsy may help to distinguish malignant from benign tumors.11 This is particularly important for mediastinal tumors which may benefit from preoperative treatment (germ cell tumors, Castleman disease, hemangiomas, and thymomas) and for tumors that are generally treated nonsurgically (lymphomas and multicentric Castleman disease). MRI is often used to determine the presence of vascular anatomy or tumor invasion and PET scan may be helpful to distinguish benign from malignant thymic conditions.12,13
|CYSTIC||FAT DENSITY||CYSTIC WITH SOLID COMPONENT||SOLID|
|Teratoma||Teratoma||Teratoma||Germ cell tumor|
|Thymic cyst||Thymoma lipoma||Thymoma with cyst||Thymoma or cancer|
|Foregut cyst||Morgagni hernia||Thyroid||Thyroid goiter|
|Parathyroid adenoma||Inflammatory disease with abscess|
|CONTRAST DELINEATION FOR DETERMINATION OF ANTERIOR AND MIDDLE MEDIASTINAL MASSES|
|Contrast enhancement||HIDA scan||PET scan||Octreotide scan|
|Parathyroid adenomas||Parathyroid adenoma|
|Mesenchymal vascular tumors|
Benign Anterior Mediastinal Tumors
Benign anterior mediastinal tumors commonly comprise benign thymic masses, endocrine tumors, teratomas (benign), lymphoid hyperplasia or uncommon mesenchymal tumors.
Benign thymic tumors consist of thymic hyperplasia, thymic cysts, thymolipomas, and lymphoepithelial thymomas. The management of diffuse thymic enlargement, if not associated with systemic autoimmune disease or parathymic symptoms, may depend on the presence or absence of symptoms which may denote true thymic pathology warranting thymic biopsy or thymectomy. In a review of asymptomatic, diffusely enlarged thymus glands, symptomatic patients were found in 22% of cases to have underlying malignancy, whereas no malignancy was found in asymptomatic patients.14
True thymic hyperplasia which is present when there is an increase in the normal components of the thymus gland and the normal organoid framework of the thymus gland is maintained. This type of hyperplasia may occur as a result of rebound thymic reconstitution following thymic depletion associated with antiretroviral therapy, following chemotherapy or stress, as an idiopathic condition, or in association with autoimmune diseases such as hyperthyroidism.15
Lymphofollicular thymic hyperplasia occurs in conjunction with increased lymphocytic B cell follicular production within germinal centers. It is associated with expanded B and T cell populations that lie outside the normal epithelial framework of the gland and is typically associated with systemic autoimmune disease such as myasthenia gravis.16
The separation of true thymic hyperplasia from lymphofollicular thymic hyperplasia is important therapeutically, since surgical resection of the thymus gland is beneficial only for hyperplasia associated with myasthenia gravis or other parathymic syndromes.17 It is recommended that surgery for thymic hyperplasia (described in Chapters 137–139) should be performed only after resolution of the hypothyroid state unless signs of malignancy are present (invasion, calcifications, cysts, or septations).18 Thymic cysts may be congenital or acquired.19,20 The congenital form is usually unilocular, whereas the acquired form is generally multilocular and accompanied by inflammation. Malignancy is uncommonly associated with thymic cysts.21,22 Thymic cysts present a clinical dilemma in distinguishing between benign thymic cysts and tumors with cystic degeneration occurring with invasive thymoma. The treatment of thymic cysts is controversial, as to whether they should be followed, aspirated, or removed. Excision is suggested if a thymic tumor cannot be excluded.
Thymolipoma is an uncommon benign hamartomatous tumor of the thymus composed of mature adipose cells and lymphoepithelial cells in various proportions. It may be associated with autoimmune-induced systemic diseases such as Graves disease, pure red blood cell neoplasia, aplastic anemia, hypogammaglobulinemia, myasthenia gravis, and Hodgkin disease. The etiology of this tumor is unknown; calcifications and cystic degeneration may occur, in the lymphoepithelial component, which may lead to the diagnosis of a mediastinal lipoma. Surgical resection is the treatment of choice which may also resolve accompanying systemic autoimmune symptoms.23,24
Substernal or intrathoracic goiter may account for anywhere between 3% and 6% of mediastinal masses. These goiters rarely receive their blood supply from mediastinal vessels.25 Surgery for mediastinal goiter is described in Chapter 136. Ectopic thyroid glands can also present in the mediastinum with compressive symptomatology.26
Parathyroid adenomas can occur in the mediastinum; 20% of patients with parathyroid adenomas have tumors that extend into the mediastinum, but most can be extracted by a neck incision. Parathyroid cysts are rare (106 cases reported worldwide)27 and usually associated with the inferior parathyroid glands; the majority occupy the middle mediastinum and the rest lay in the anterior mediastinum. These cysts are classified as functioning or nonfunctioning on the basis of elevated serum parathyroid hormone levels.27 Mediastinal and neck exploration is necessary for functioning ectopic mediastinal parathyroid adenomas or cysts, which occur in 2% of patients; such glands may be reached by thoracoscopic exploration.28 Nonfunctioning parathyroid cysts can be either removed, aspirated, or sclerosed1,27; removal is recommended for all functioning cysts and those that are large enough to cause compressive symptoms or recur after aspiration. Accurate preoperative localization of these glands can be obtained with selective venous sampling for parathyroid hormone levels, technetium sestamibi scans, CT scans of the chest and neck, or combined sestamibi CT scans which, if positive, also can aid with intraoperative localization by gamma probe thoracoscopic identification of the tumor. Confirmation of tumor removal may be achieved by intraoperative parathormone assay.29,30
Paragangliomas are sympathetic and parasympathetic chromaffin cells are derived from their associated paraganglioma. Between 10% and 50% are hereditary and may be associated with neurofibromatosis type I, von Hippel–Lindau syndrome, Carnery syndrome, and rarely multiple endocrine neoplasia type II. Germline mutations in three genes encoding subunits of succinate dehydrogenase (SDH) or mitochondrial complex II are associated with the familial form of this disease. In particular, one subunit (SDH B) is associated with a malignant form of this disease,31 although malignancy can occur in the absence of this gene mutation.32 This tumor can present in a cystic form33 either with or without hypertension from catecholamine release, and it is highly vascularized and predominantly occurs in the anterior and middle mediastinum.33,34 Surgical resection may be extensive and may require both α blockade and cardiopulmonary bypass.34,35
Teratomas account for 5% to 10% of all mediastinal tumors, with 95% occurring in the anterior mediastinum (primarily found in the thymus)16,36 and 3% to 5% in the posterior mediastinum.37,38 In the pediatric population, 7% of germ cell tumors are found in the mediastinum while it is the most common site for extragonadal germ cell tumor in adults There is no sex predilection, and most patients present without symptoms with large tumors16 Benign teratomas include mature teratomas (45%–75% of patients), mature teratomas with immature elements comprising less than 50% of the volume, and immature teratomas, which occur almost exclusively in patients younger than age 15.5,39 Symptoms related to these tumors usually include pain and occasionally cough, with the possible expectoration of hemoptysis, hair, or sebum.37 Complete excision of mediastinal teratomas is strongly desired to prevent malignant somatic transformation of teratomatous elements40 or the complications of compressive conditions or chronic fistula formation with infection.41 Resection of these tumors may be difficult to do by a VATS approach because of dense adhesions to neighboring structures and the need for adequate incisions for large tumor delivery.37 The prognosis for cystic teratoma containing immature or malignant elements is age-dependent; in the pediatric population these tumors behave in a benign fashion; however, they can be very aggressive in adults.16,36
Castleman disease is a benign form of marked lymph node hyperplasia caused by human rhadinovirus infection of the B-cell population, usually occurring in the mediastinum (70% of patients); it commonly occurs in the anterior compartment, but it can occur in any lymphatic area or rarely in nonnodal areas.42,43 Histologically, it is divided into the hyaline-vascular form (91% of patients, commonly in a solitary location) and the plasma cell form (9% of patients, likely found in multicentric locations). These tumors are unusual and may portend other malignancies such as Kaposi sarcoma and lymphoma, which are strongly associated with HIV positive patients.44 The unicenter hyaline-vascular form usually is benign, and recurrence occurs only rarely after complete surgical removal, although vascular neoplasms and occasionally lymphomas may occur in long-term follow-up.42,43,45 The plasma cell variant is often multicentric and aggressive, particularly if associated with HIV positive patients.44 Its proliferative potential may be attributed to high levels of the cytokine interleukin 6, which may induce Kaposi-like endothelial vascular neoplasms and lymphomas. The solitary and multicentric plasma cell forms of Castleman disease are strongly associated with infection by human herpesvirus 8, which may induce interleukin 6 production by virally encoded particles into native strands of DNA.45,46
Surgical resection, is the primary treatment of the localized forms of both types of Castleman disease. Preoperative angiography and embolization may be helpful to reduce the increased vascularity of these tumors.42,43 Surgery for the multicentric form of this disease is limited to biopsy provision for pathologic determination or possibly debulking for early-stage disease combined with rituximab and chemotherapy.44 Antihuman monoclonal antibodies against interleukin 6 and anti-CD20 monoclonal antibodies against CD20+ B-lymphocytes are potential treatment strategies for the multicentric variant of Castleman disease, once the diagnosis is confirmed histologically.42,47 Other potential molecular targets for this disease are human herpesvirus 8 and angiogenesis factors.47Both variants of the disease require long-term surveillance for vascular tumors or lymphomas.