CHAPTER 9 Mediastinum
Clinical aspects
A broad range of mass lesions is found in this site, of which about 40% are malignant. Two major factors in the incidence of different entities are the age of the patient at presentation and the mediastinal compartment in which the mass arose and appears radiographically. Tumors in children are more likely to be neurogenic neoplasms, enterogenous cysts, teratomas, vascular lesions or lymphomas. In adults, the most common mass lesions are metastases and cysts of thymic, pericardial or enteric origin, followed by thymomas, neurogenic tumors, lymphomas and germ cell tumors.1–3
Lesions of the anterior/superior mediastinum are more likely to be thymic epithelial neoplasms, thymic cysts, lymphoma, thyroid and parathyroid proliferations and germ cell tumors. Of those in the middle mediastinum, lymphoma and pericardial or bronchogenic cysts predominate. Masses in the posterior mediastinum consist mostly of nerve sheath or neuronal tumors and bronchogenic or enteric cysts.1–3
Clinical and laboratory findings may be helpful. For example, such clues include the presence of high levels of circulating human chorionic gonadotrophin (beta-hCG) and alpha-fetoprotein in certain germ cell tumors, myasthenia gravis (although recall that myasthenia is more commonly associated with follicular hyperplasia of the thymus), red cell aplasia, hypogammaglobulinemia in thymoma, and Cushing’s syndrome in carcinoids.1–3
Most lesions are illustrated in other chapters.
The place of FNAC in the investigative sequence
Fine needle aspiration has long been used for the confirmation of metastatic disease and is increasingly accepted as the basis for the management of primary mediastinal malignancies. After imaging, FNB is generally the first-line diagnostic method, although some suggest that core biopsy gives higher rates of specific tumor typing for lymphoma, thymoma and neural tumors (at the cost of lower sensitivity).4,5 Mediastinoscopy and open thoracotomy and biopsy are still necessary for some primary lesions, particularly Hodgkin lymphoma, rare lesions such as sarcoma where architectural features may be necessary for a fully specific diagnosis or where the initial material is insufficient for immunochemistry, ultrastructure, cytogenetics or molecular analysis, although all of these techniques may be applied to material obtained by FNB. Endoscopic ultrasound (EUS) guided FNB via the transoesophageal or transbronchial routes has become an indispensable method of identifying lymph node metastases in lung cancer diagnosis and staging, and in mediastinal lesions out of the reach of transbronchial or transtracheal sampling.6–10 Occasionally we have experienced difficulty in verifying the exact site of origin of malignant cells in such specimens as a result of contamination of the sample by malignancy derived from the primary tumor in bronchus or esophagus,11 despite the use of stilettes. This may limit the use of the technique for staging in some cases. However, one good rule of thumb is that a true metastasis is supported when one microscopically witnesses an intimate admixture of malignant cells and reactive lymphoid elements, especially germinal center fragments.
The selection of cases for EUS-FNB has been the subject of recent study. Eltoum et al. suggest that careful evaluation of pre-test probability of malignancy may help in deciding which patients are likely to benefit from EUS-FNB.12
Mediastinal infections are amenable to diagnosis by FNB,13 as is sarcoidosis.14
Accuracy of diagnosis
Most cancers will be diagnosed as malignant, and accurate tumor typing is often possible.15–37 For example, a diagnosis of a specific germ cell tumor can be achieved with clinical data and conventional cytomorphology supplemented with a small panel of antibodies.25,36 For example, whereas germinomas yield a highly characteristic cytologic picture, embryonal and endodermal sinus carcinomas are less specific-appearing.
It is often difficult to obtain material from sclerotic lesions such as nodular sclerosing Hodgkin lymphoma by fine needle alone, but a combination of cytology and cell blocks or thin core sampling can give diagnostic material.37 For the non-Hodgkin lymphomas, a specific diagnosis is possible for many lymphomas using a combination of cytomorphology, immunophenotyping by either flow cytometry or immunochemistry on cytospins, cell blocks or thin cores, and at times genetic and cytogenetic tests.38
Powers et al.25 reported a large multi-institutional study of 189 FNA cases with a sensitivity of 87% and a positive predictive value of 97% for a diagnosis of neoplasm. Metastatic small cell carcinoma was the commonest neoplasm, followed by lymphoma and thymoma as the commonest primary tumors. Singh et al.39 reviewed material from the same institutions, looking specifically at diagnostic pitfalls including 12 cases with discordant cytology and follow-up histology. These included small cell carcinoma resembling lymphoma, Hodgkin lymphoma and large cell lymphoma with prominent spindle cell components suggesting a connective tissue neoplasm, large cell lymphoma diagnosed as Hodgkin lymphoma, thymoma resembling large cell lymphoma, clear cell adenocarcinoma where the possibility of germ cell tumor was raised, thymic carcinoma with insufficient tissue to distinguish from benign thymoma, ectopic thyroid resembling metastatic carcinoma or carcinoid, and a breast carcinoma with a squamous appearance. Sparse cellularity was a contributing factor in most cases and the recommendation for biopsy for definitive typing was often made. Assaad et al. reviewed the results of 157 CT-FNB and were able to make definitive diagnoses in 82% of cases with a high concordance with subsequent histological diagnoses.40 Geisinger reviewed the range of pitfalls and problems which may be found in cytodiagnosis in this site.41
Khan et al. showed 66% sensitivity in the diagnosis of tuberculosis compared with 20% for fibreoptic bronchoscopy.13
Complications
The complications of aspiration of this site are no more frequent than in FNA of the lung. Even when superior vena caval obstruction is present, aspiration appears to be very safe, and is the procedure of choice.16,17,22,24 CT has particular value in this site, as it can localize the needle tip within the lesion far better than fluoroscopy,16,17 and thus rare complications such as cardiac tamponade can be avoided. Prior CT scanning is used to exclude aneurysm and delineate relationships with adjacent structures, including large vessels. Endoscopic ultrasound (EUS) guided FNA by the transoesophageal and transbronchial routes has further reduced the risk of bleeding or other complications.7 Nevertheless, as with all deep aspirates, there may be complications. Von Bartheid et al. documented a mediastinal-oesophageal fistula after FNB of TB.42 Aerts et al. reported a case of mediastinitis after puncture of a necrotic metastatic malignancy in a node.43 Doi et al. describe needle track tumor implantation in the oesophageal wall after EUS. The clinical background of each case must be considered before embarking on the procedure.44
Technical considerations
Obtaining material
Direct FNB is carried out using fluoroscopic, ultrasound45 or CT guidance, including transthoracic46 and suprasternal47 approaches. Transbronchial or transcarinal FNB is especially useful in diagnosing and staging metastatic disease, but may also reveal primary lesions.7–9,47–50 Endoscopic ultrasound guided FNB has rapidly become an essential tool in the staging of lung carcinomas because of the precision with which needles can be directed into nodal metastases.7–9 It may be used by transoesophageal or transbronchial routes.7–9 Mediastinal cystography yields a strong guide to the nature of cysts.51 Fibrosis and non-specific chronic inflammation sometimes prevent adequate sampling and even mediastinoscopy may not be successful. However, we have found FNA samples to be better than core biopsies on numerous occasions and believe this should be the first-line method, with supplemental material for other tests being based on initial cytological assessment. The thin needle may track into cellular areas better than cores and samples material over a wider area. With the pathologist at the procedure, FNB and core biopsy become complementary. One can evaluate touch preparations of cores at the time of procurement to assess their adequacy, and even assist in diagnosis.
Ancillary testing (Table 9.1)
Our approach to diagnosis is similar to that in other deep sites. The pathologist is present at the aspirate with a microscope to confirm adequacy of material and to prepare for appropriate ancillary studies. We rely particularly on cell-block preparations and immunocytochemistry due to the extraordinary variability of neoplasms of this site; cytological features alone are often not sufficient for the specific diagnosis of some primary tumors. Either repeated aspiration passes or core biopsy using automatic sampling devices is a very useful way of obtaining additional material for ancillary tests and/or for architectural analysis. Neill and Silverman52 and Taccagni et al.53 emphasized the value of ultrastructural diagnosis, particularly for thymoma, germ cell tumors, carcinoid tumors and small cell carcinoma. However, today EM is being supplanted by immunophenotyping due to the expense of EM, the greater sampling error with EM, and the much greater availability of immunochemistry. For example, Akhtar et al.36,54 and Singh et al.39 see immunocytochemistry as necessary for confirmation of germ cell tumor type. Immunocytochemistry or flow cytometry are routinely used for diagnosis and typing of non-Hodgkin lymphomas (see Chapter 5). Powers et al. used ancillary tests in 27% of their cases.25,39 Herman et al. noted lower sensitivity and ability to type tumors accurately in the period before the use of ancillary tests.23
Table 9.1 General outline of ancillary tests in the differential diagnosis of mediastinal tumours1–376
It was hoped that molecular analysis may help pinpoint the site of origin in patients with tumors of unknown origin,55–57 although recent applications of molecular analysis have turned to its use in targeted drug therapy rather than specific tumor typing.
Cytological findings
The mediastinum is a common site of metastasis for neoplasms from all sites. In FNA samples, small cell carcinoma of lung is the most frequent metastasis, with lesser numbers of non-small cell tumors of lung, followed by breast carcinoma.25 Metastatic sarcomas may also be seen, but remember the possibility of origin from a germ cell tumor if a malignant spindle cell neoplasm is encountered. Rare primary sarcomas may also be seen.
Baker et al.58 suggested that in sampling mediastinal nodes by the transbronchial route, lymphocytes are necessary to confirm specimen adequacy, otherwise bronchial contents may be misinterpreted as originating from mediastinum. As stated above, we agree.
Thymoma (Figs 9.1–9.6)18,25–35,59–63
Fig. 9.5 Thymoma, spindle cell
Cohesive tissue fragment; elongated pale, regular nuclei; indistinct cell borders (H&E, HP oil).
Criteria for diagnosis
In the benign thymomas, the epithelial cells are usually cohesive (Figs 9.1, 9.5) but may also manifest a reduction in intercellular cohesion (Fig. 9.2). Epithelial cells are not immediately evident in the mixed tumors at low power but are discernible using the higher magnification.18,29,30 The epithelial cells are polygonal, oval, or spindle shaped with uniform to slightly irregular nuclear outlines possibly with cleaved or folded nuclei. Their nuclear chromatin is homogeneous, finely distributed and pale and, occasionally, small nucleoli are seen. Cell borders are indistinct, but nuclei are separated by moderate amounts of pale cytoplasm (Figs 9.2, 9.5). In one personally examined case of thymoma metastatic to lung, Hassall’s corpuscles were evident in the clumps of tumor cells (Fig. 9.4); this is a most unusual manifestation and will not be present in most thymomas. When there is a lymphoid population, the bimodal pattern enables one to make a virtually certain diagnosis.18,29,30 In pure epithelial or spindle cell forms, definitive diagnosis is more difficult, although in Dahlgren’s series29 most thymomas were diagnosed and in Tao’s 37 cases30 all FNAC diagnoses of thymoma were verified histologically. Ali and Erozan34 were able to diagnose all of their 14 cases using a combination of cytology, immunocytochemistry and clinical information, and Shin and Katz showed a high accuracy in a range of mediastinal lesions including 14 thymomas.35 Tao and others describe more variation in the degree of cohesion than we have seen, particularly in pure epithelial/nonspindle cell types.30 Overall, the most challenging and the most common in our experience are the lymphocyte-rich (type B1) thymomas, as the tumor cells may be obscured by the lymphocytes.
Large cell lymphoma with sclerosis may yield cohesive fragments of tissue, resembling lymphocyte-rich thymomas. Immunophenotyping for lymphoma and ultrastructural or immunoperoxidase demonstration of an epithelial component in thymoma will help resolve the differential diagnosis. The clinical background may be misleading, as in a case of malignant thymoma in an HIV-positive patient.64 Lymphoma cells compressed within collagen may resemble a spindle cell neoplasm.
Type B1 thymomas contain lymphoid cells of immature thymic type. These may be selectively sampled and give a false impression of lymphoma, especially lymphoblastic lymphoma. Similarly, if material is submitted for flow cytometry, the immature T phenotype may cause confusion. However, a maturing T-cell phenotype is characteristic of thymoma and thus is quite helpful in this situation. The immature cells demonstrate CD1, 2, 4, 5, 7 and 8 positivity and TdT, representing the common or intermediate stage of thymocyte differentiation, a profile similar to that of T-lymphoblastic lymphoma.65 Some cases also demonstrate apparent ‘loss’ of various T-cell markers, heightening a suspicion of T-cell lymphoma. In our experience, unless the cytologist reviewing material either in the radiology theatre or in the lab alerts the haematology laboratory to the likelihood of lymphocyte-rich thymoma, there is a very real risk of false-positive diagnosis of lymphoblastic lymphoma by flow cytometry.
Other spindle cell lesions within the mediastinum include benign and malignant connective tissue neoplasms, reactive processes with or without associated neoplasms, granulomas, mesothelioma, melanoma, spindle cell squamous carcinoma and spindle cell carcinoid.66,67 Connective tissue neoplasms may be cohesive but, especially in neural tumors, have a more abundant and more myxoid stroma than thymomas. Spindle cell squamous carcinoma shows cytological features of malignancy lacking in thymoma; however, primary spindle squamous carcinoma of the thymus (a form of thymic carcinoma) is described. An approach which includes ancillary testing in all cases will help prevent error.
Sometimes, non-neoplastic thymic epithelium may be included in an FNB sample and give rise to erroneous tumor typing. Yu et al.45 described a case of large cell lymphoma in which this occurred and then demonstrated entrapped thymic epithelium in a third of their cases of surgically excised large cell lymphomas. There was reactive proliferation of the epithelium in some cases. Thymic hyperplasia may completely mimic thymoma in smears.68,69
Malignant thymoma (Figs 9.2, 9.7 and 9.8)1–3,18,25,64,70–74
Thymic carcinomas are very uncommon cytologically malignant tumors with a wide variety of morphological appearances including keratinizing and nonkeratinizing squamous, sarcomatoid, anaplastic large cell, basaloid, mucoepidermoid, clear cell and small cell types.1–3 A cytological diagnosis of carcinoma may be made by FNB. Smears are variably cellular and usually dominated by loosely cohesive large malignant cells diagnostic of carcinoma. Most are composed of large tumor cells with solitary clearly malignant nuclei, with or without prominent nucleoli. As expected, their smear appearance resembles the underlying histopathology. Reports of FNB diagnosis of rare subtypes such as basaloid and mucoepidermoid carcinomas area also reported.73,74
Anaplastic carcinoma from other sites is not distinguishable from primary thymic carcinoma on cytomorphology alone. Dorfman et al.75 found CD5 positivity in tumor cells to be characteristic of primary carcinomas, in contradistinction to benign thymomas and carcinomas from other sites. Newer markers such as Foxn1 and CD205 may also prove useful.76
A histogenetic classification of thymomas has been accepted by some (see above).1–3 The older classification (spindle, lymphocytic, epithelial and mixed) and the newer subgrouping (medullary, mixed, predominantly cortical (organoid), cortical and well-differentiated thymic carcinoma) both have prognostic relevance.2,3,77 The subtypes in these two systems can be related histologically2,3 although cytological findings alone may not allow accurate prediction of tumor type. Some authors still advocate a simple morphological classification into thymoma, atypical thymoma and thymic carcinoma.78 All authors acknowledge that staging is a crucial aspect of assessment of biological behavior.1–378 Shimosato et al. trace the conceptual evolution of thymoma and thymic carcinoma classification and staging.1
Neuroendocrine neoplasms66,79–86 (see also Chapter 8)
Primary neuroendocrine tumors of the mediastinum include carcinomas ranging from low to high grade (carcinoid, atypical carcinoid, large cell carcinoma, and small cell carcinoma).1–3 Cytomorphologic criteria for diagnosis are quite similar to those in other sites, especially the lung. Although there is a spectrum of biologic behavior correlating with grade, even apparently low-grade neoplasms may show very aggressive clinical behavior in the mediastinum.83–85 Furthermore, tumors with combined low-grade and high-grade morphologic attributes occur with some relative frequency.84 The low-grade ones may also produce paraneoplastic syndromes, especially Cushing’s syndrome. When combined with the characteristic radiologic finding of focal calcifications, this may suggest the diagnosis prebiopsy. These tumors are associated with multiple endocrine neoplasm syndromes in about 25% of cases, usually type 1.87 Gherardi describeed intracytoplasmic paranuclear keratin inclusions similar to those seen in Merkel cell tumors, small cell carcinoma and other neuroendocrine neoplasms in three cases sampled by FNB.79 These structures were best demonstrated in Romanowsky stains as optically clear paranuclear spaces, confirmed by cytokeratin staining in smears, along with Grimelius staining, NSE positivity and Leu-7 or chromogranin staining in several cases. Paranuclear apoptotic material was also observed in some cells and there was discohesion, mitotic activity, single cell necrosis and tingible body macrophages in the background, producing a resemblance to lymphoma. Lymphoglandular bodies were not seen. Wang et al. diagnosed four cases of thymic carcinoid tumor without atypical features.80 They found Riu’s stain or argyrophilia useful for identifying neurosecretory granules in the cytoplasm. One patient had Cushing’s syndrome and the tumor cells demonstrated ACTH positivity. In Dusenbury’s case, the diagnosis was made by cytology and positive synaptophysin staining.66 A spindle cell component was described. Smith et al. diagnosed an unusual lipid-rich carcinoid tumor by FNA.86
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