Mediastinum
Louis P. Dehner
I. GROSS ANATOMY. The mediastinum is located in the thoracic cavity and is generally divided into superior, anterior, middle, and posterior compartments and is bounded by the pleura laterally. Generally, the first rib defines its superior limit and the diaphragm its inferior border. The sternum, ribs, and thoracic vertebrae (T1 through T11-12) constitute the skeletal confines of the mediastinum. The thymus, heart and great vessels, lungs, and esophagus are among the most obvious organs which occupy the anterior (thymus), middle (heart), and posterior (esophagus and aorta) mediastinum. The aortic arch and the proximal segment of the aorta (ascending and proximal aorta) are located in the superior mediastinum, which is bounded by the manubrium sterni anteriorly and thoracic vertebrae 1 through 4. The embryological aspects of the mediastinum are basically those of the organs and structures which occupy this compartment.
The definition of the mediastinum relates to the structures and organs with observable pathology on imaging studies and the associated differential diagnosis. For instance, the anterior mediastinum is the site of the thymus with its varied associated pathology from Hodgkin and non-Hodgkin lymphoma (NHL), to thymoma, to germ cell neoplasms. The pathology of the posterior mediastinum is dominated by a variety of neurogenic neoplasms and bronchoenteric developmental cysts.
II. GROSS EXAMINATION, TISSUE SAMPLING, AND HISTOLOGIC SLIDE PREPARATION
A. Fine needle aspiration (FNA) biopsy. FNA is generally performed as an imageguided or endoscopically directed procedure on suspected pathology in the anterior or middle mediastinum. These specimens are processed in the same manner as other FNA specimens, and are commonly examined for adequacy so that the results can be transmitted contemporaneously with the procedure. Given the broad range of pathologic processes in the anterior and middle mediastinum, an advanced level of experience is recommended for FNA interpretation of specimens from these sites.
One of the more common specimens is a lymph node with the differential diagnosis of an infectious and/or granulomatous process, metastasis, or lymphoma. Metastasis, usually a carcinoma of the lung or elsewhere (most often squamous cell carcinoma of the head and neck, papillary thyroid carcinoma, or renal cell carcinoma), accounts for over 50% of the diagnoses. NHL (lymphoblastic lymphoma and mediastinal large B-cell lymphoma) and Hodgkin lymphoma (HL) are the most common primary malignant neoplasms of the mediastinum; however, while strong suspicion about an NHL can be voiced in the case of a lymphoblastic lymphoma, both the large B-cell lymphoma and HL of the nodular sclerosis subtype have a considerable fibrous component, which may complicate the ability to obtain a sufficiently cellular FNA specimen for diagnosis.
Biopsy. Tissue samplings from the anterior mediastinum are generally small (<1 cm) and often consist of multiple fragments which have been obtained via mediastinoscopy. These specimens, commonly intrathoracic lymph nodes, are submitted for intraoperative frozen section consultation to ascertain their metastatic status for purposes of operability of a nonsmall cell carcinoma of the lung. Often biopsies that show no evidence of malignancy contain granulomas in varying stages of activity and type (including the so-called naked granulomas of sarcoidosis), or simply a carpet of pigmented macrophages.
Mediastinal biopsies in those cases with a clinical suspicion of a disease process other than the metastatic carcinoma present the intraoperative dilemma of performing a frozen section or not when the biopsy consists of only a small amount of tissue; however, a discussion with the surgeon is helpful in these cases. When lymphoma is suspected, tissue should be set aside for flow cytometry, but necrosis and fibrosis often limit the evaluation. When the lymphoma is a suspected HL, every fragment of the tissue is critical in the search for Reed-Sternberg cells and their subsequent confirmation by immunohistochemistry (in this case, prospective sectioning through the entire formalin-fixed paraffin tissue block is recommended, with mounting of the unstained sections for additional studies; however, the alternative approach of returning to the block later results in a high risk of loss of potentially diagnostic tissue during refacing of the block).
Both benign and malignant processes in the mediastinum may be accompanied by a substantial fibroinflammatory reaction, which encases the underlying pathology. It is therefore necessary in these cases to recommend a re-biopsy when the only findings are those of chronic inflammation and fibrosis.
B. Resection. Surgical resections of mediastinal contents are restricted in most cases to mass lesions in the anterior mediastinum with thymic-related neoplasms, the thymus gland in cases of myasthenia gravis or a germ cell neoplasm (which may or may not be associated with the thymus). An enlarged substernal adenomatous thyroid or parathyroid adenoma may also present in the anterior superior mediastinum; however, the examination of these latter two specimen types should follow the recommendation in Chapters 24 and 25, respectively. The other compartments with resectable specimens include foregut cysts of the middle mediastinum (most commonly a bronchogenic cyst) and enteric duplication cysts of the posterior mediastinum, as well as the entire morphologic spectrum of neurogenic neoplasms from neuroblastoma to schwannoma and paraganglioma (as discussed below).
A resected thymus may be represented by nondescript fibroadipose or adipose tissue which upon sectioning fails to demonstrate any mass lesion (Thorac Surg Clin. 2011;21:191). On the other hand, a mass lesion may be clearly evident by its size, shape, and weight; these three characteristics should be noted upon the initial gross examination before any sectioning takes place. The external surface should be described as to whether it is smooth and/or glistening, or irregular by virtue of apparent fibrosis; the latter may reflect the presence of adhesions between the mass and contiguous structures such as the pericardium, lung, or pleura which may be included as part of the resection specimen. Because surgical margins are important in pathologic staging, especially in the case of a thymoma, the surface of the tumor should be marked in such a manner that the resection margins can be identified microscopically. If the superior and inferior poles of the specimen can be identified, then the specimen can be bisected along that plane and the surface exposed to describe the salient features including any apparent capsule or pseudocapsule; circumscription or lack thereof; diffuse or lobulated appearance; uniform or heterogeneous character; solid, solid and cystic, or cystic appearance; hemorrhage or necrosis; and any identifiable portion or remnant of uninvolved organs. The selection of blocks for microscopic section should include a thorough sampling of the margins; sections of the apparent tumor should include any regional variations in the appearance of the mass.
If the mass is predominantly cystic, the differential diagnosis is teratoma, thymic cyst, or cystic thymoma. A solid, or solid and cystic, mass may represent a thymoma, thymic carcinoma, seminoma, or mixed germ cell neoplasm, HL, Castleman disease (CD), mediastinal large B-cell lymphoma, Langerhan cell histiocytosis, granulocytic sarcoma (acute myeloid or monocytic leukemia), or localized sclerosing-fibrosing mediastinitis.
III. MEDIASTINAL SOFT TISSUES
A. Inflammation (mediastinitis)
1. Acute and chronic inflammation. Acute mediastinitis with a purely neutrophilic reaction is a consequence of a contiguous infection, rupture-perforation of the esophagus, penetrating trauma, congenital duplication, or foregut cyst (Thorac Surg Clin. 2009;19:37). A peritonsillar abscess, suppurative thyroiditis, periodontal abscess, and post-sternotomy infection, notably by methicillin-resistant Staphylococcus aureus, are other causes. In addition to the acute inflammatory reaction, the tissues may have a necrotizing appearance especially in those cases with the spread of an infection from the head and neck region into the mediastinum by the so-called acute descending necrotizing mediastinitis (Heart Lung Circ. 2008;17:124). With the passage of time, acute inflammation is accompanied by a mixed inflammatory response with macrophages, a fibroblastic reaction, and microvascular proliferation.
2. Chronic fibroinflammatory process (fibrosing-sclerosing mediastinitis). This uncommon but well-documented clinicopathologic entity comes to attention with a persistent cough and fever in young to middle-aged adults (Semin Respir Infect. 2001;16:119). A mass lesion is usually present in the right paratracheal or subcarinal region, often associated with punctuate calcifications. Less frequently, the presentation is as more diffuse infiltrative mass, which is no longer confined to the middle mediastinum. An abnormal host response to the antigens of Histoplasma capsulatum is thought to account for cases in regions endemic for the infection. A needle or wedge biopsy is the usual type of specimen for pathologic evaluation. Infrequently, fibrosclerotic lesions may be present elsewhere in the mesentery or retroperitoneum as manifestations of the IgG4-related diseases (Am J Surg Pathol. 2010;34:211).
There are several microscopic stages through which this fibroinflammatory process evolves from a reactive fibroblastic stage with an edematous background resembling nodular fasciitis, to a dense hyalinized collagen stage of the interstitium and thickened blood vessels showing similar hyalinized features (e-Fig. 10.1).* A dispersed population of lymphocytes and plasma cells is present throughout the biopsy. Granulomas are not a feature in most cases despite the association with Histoplasma. Dystrophic calcifications may or may not be present. A similar pathologic process occurs in the lung as pulmonary hyalinizing granulomas.
The differential diagnosis includes HL and NHL, inflammatory myofi-broblastic tumor, calcifying fibrous pseudotumor, and fibromatosis (desmoid tumor). Appropriate immunohistochemical studies are helpful in the differential diagnosis if diagnostic or suspected cells are found in the biopsy (Table 10.1).
3. Granulomatous mediastinitis. A number of infectious etiologies are responsible for granulomatous inflammatory reactions in the mediastinum. It is generally the case that other sites in the thoracic cavity including the lungs and regional lymph nodes also harbor the particular infection, which is usually either tuberculous or fungal in nature. The active, infectious granulomas show the presence of caseous necrosis. The granulomas are hyalinized with or without dystrophic calcifications when the infection is inactive. The most common organism in addition to Mycobacterium tuberculosis is H. capsulatum; other rare causative fungal organisms include Cryptococcus, Blastomyces, Coccidioides, and the Rhizopus group. Sarcoidosis typically involves hilar lymph nodes without direct involvement of the mediastinal soft tissues,
except in rare cases (Respiration. 2010;79:341). HL of the nodular sclerosis type may have a prominent granulomatous reaction which can overshadow the isolated Reed-Sternberg cells.
TABLE 10.1 Immunohistochemical Phenotypes of Fibroinflammatory Lesions of the Mediastinum
CD15
CD30
ALK1
Smooth muscle actin
Factor XIIIa
Fibrosing mediastinitis
−
−
−
±
−
Hodgkin lymphoma
+
+
−
±
−
Inflammatory myofibroblastic tumor
−
−
+
+
−
Calcifying fibrous pseudotumor
−
−
−
±
+
Mediastinal large B-cell lymphoma
−
+
−
−
−
Fibromatosis (desmoid)
−
−
−
+
−
IV. MEDIASTINAL NEOPLASMS. Intrathoracic, extrapulmonary, and nonmetastatic neoplasms arising in one of the mediastinal compartments qualify as uncommon to rare in the general experience of most institutions. No more than 5% to 10% of the intrathoracic neoplasms originate in the mediastinum independent of the lung, heart, and great vessels. However, the different tumor types are a microcosm of neoplasms, which are seen not only in intrathoracic sites, but also in extrathoracic organs and locations (Lancet Oncol. 2004;5:107). The distribution and frequency of the different types of mediastinal tumors relate to the definition of particular lesions as neoplastic or nonneoplastic, especially in the case of some of the cysts, and whether the series includes both benign and malignant tumors or only the latter. Approximately 30% to 35% of the mediastinal tumors are derived from thymic epithelium, followed by HL and NHL (25% to 30%), germ cell neoplasms (10% to 15%), neurogenic tumors (10% to 15%), and a miscellaneous category (15%) consisting of soft tissue neoplasms of virtually all types. If discussion is limited to those mediastinal tumors presenting in the first two decades of life, the general experience is that HL and NHL account for 40% to 80% of the cases, with neurogenic (20% to 25%) and germ cell (15% to 20%) neoplasms accounting for the remainder (Semin Thorac Cardiovasc Surg. 2004;16:201; Thorac Surg Clin. 2009;19:47). Nongerm cell thymic neoplasms are rare in children, but a variety of soft tissue neoplasms exclusive of schwannoma are, however, observed in this age group. The WHO classification of mediastinal tumor is shown in Table 10.2.
A. Thymic neoplasms. This category of neoplasms includes thymoma, thymic carcinoma, and neuroendocrine carcinoma including thymic carcinoid. These tumors arise from the thymic epithelium. Within the category of thymic neoplasms, approximately 80% to 85% are thymomas, 10% are thymic carcinomas, and 5% are pure neuroendocrine carcinomas.
1. Thymoma. Many approaches to the pathologic classification of thymoma have been taken, surprising in that thymomas are an uncommon category of neoplasm whose estimated incidence is <0.15 per 100,000 person-years. In thymomas, the neoplastic thymic epithelium usually appears deceptively bland even though the tumor may have invaded surrounding anatomic structures and even metastasized; tumors that have histologic features of a carcinoma in the traditional sense of cellular enlargement with hyperchromatic and mitotically active nuclei are classified as thymic carcinoma (see below). Considerable data are available on the molecular genetics of thymic neoplasms which broadly correlate with the histologic type of thymoma or thymic carcinoma (J Thorac Oncol. 2010;5:S313; J Thorac Oncol. 2010;5:S286).
Thymomas are neoplasms which tend to maintain to a greater or lesser degree the overall architectural and mixture of cell types, which are present
in the normal thymus (e-Figs. 10.2 and 10.3). Most thymomas have a multilobular growth pattern which is accentuated by the presence of fibrous bands that enclose the epithelial islands (e-Fig. 10.4). In the past, thymomas were differentiated on the basis of the prominence of the lymphocytic and/or epithelial elements. This descriptive classification was systematized in the World Health Organization (WHO) classification into a series of letter designations which denote the morphology (i.e., type) and in turn
correlate with the prognosis (Table 10.3), although pathologic staging in some studies is the more significant determinant of outcome. There is also some correlation between the WHO type and the locally aggressive behavior with invasion into or through the capsule. Types A, AB (e-Fig. 10.5), and B1 demonstrate invasive features in approximately 10%, 40%, and 45%, respectively whereas types B2 and B3 (e-Fig. 10.6) are invasive in 70% and 85% of the cases, respectively. Although uncommon, type A (e-Fig. 10.7) or spindle cell thymoma may demonstrate invasive behavior (Am J Clin Pathol. 2010;134:793). Thymic carcinoma or type C is regarded as separate and distinct from thymoma, and for this reason not all clinical series of thymic neoplasms include type C; similarly, neuroendocrine carcinoma (or thymic carcinoid as it was initially designated) is classified as an entity separate from thymic carcinoma.
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