Pathology of mediastinal tumors

INTRODUCTION — Mediastinal tumors are among the most difficult lesions examined by the surgical pathologist for several reasons. First, many different types of lesions occur in this location (figure 1 and table 1) [1]. Second, biopsies often consist of small, crushed specimens. Third, few pathologists have significant experience with mediastinal pathology because specimens from this location are relatively uncommon.

Since many tumors that occur in the mediastinum have overlapping histologic features, one must consider a broad differential diagnosis and perform a thorough evaluation of each specimen, which may include ancillary testing. This is important since therapy for various mediastinal tumors differs considerably and may significantly impact survival. Additionally, it may not be apparent whether the tumor is arising in the mediastinum or from adjacent lung, or might be metastatic to the mediastinum.

Interpretation of pathologic specimens from the mediastinum requires familiarity with a wide range of neoplasms and careful clinical correlation. It is critical for surgeons, radiologists, and pathologists to communicate well. If tumors originally treated by nonsurgical means do not respond as expected, additional biopsies, special studies, or consultations may be necessary to achieve the correct diagnosis.

The pathology of mediastinal tumors is reviewed here. The clinical evaluation of mediastinal masses is discussed elsewhere, and clinical and management issues of the specific tumor types are reviewed in the relevant topics.

●(See "Approach to the adult patient with a mediastinal mass".)

●(See "Clinical presentation and management of thymoma and thymic carcinoma".)

●(See "Thymic neuroendocrine (carcinoid) tumors".)

●(See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

●(See "Hodgkin lymphoma: Epidemiology and risk factors".)

ISSUES WITH EXAMINATION OF SPECIMENS — Obtaining an adequate biopsy specimen can be a problem in the diagnosis of mediastinal tumors. As some mediastinal tumors are not treated surgically (eg, lymphoma) or undergo neoadjuvant therapy before resection, diagnosis is often attempted with core needle or minimally invasive surgical biopsies. Biopsies may be nondiagnostic because the lesion is not sampled adequately or because crush artifact or extensive necrosis, fibrosis, or cystic change obscures the diagnostic lesion. (See "Approach to the adult patient with a mediastinal mass".)

Intraoperative frozen sections are often used in the setting of surgical procedures:

●To determine if diagnostic tissue has been obtained

●To establish the diagnosis so that optimal surgical treatment can be rendered

●To assess resection margins and stage of the tumor

While some tumors can readily be diagnosed by frozen section, there are many "mimickers" in mediastinal pathology that can cause diagnostic difficulties [2]. Frozen section processing may introduce artifacts. Therefore, additional tissue that is not submitted for frozen sectioning may be necessary in some cases. If the tumor is extensively fibrotic or necrotic, generous sampling may avoid the need for additional biopsy procedures. It can be useful to set aside a piece of tumor to be snap-frozen for certain molecular and/or genetic analysis.

THYMOMA — Thymomas are malignant epithelial neoplasms arising in the thymus; these tumors are commonly located in the prevascular mediastinum [3,4]. However, thymomas can also be found in other regions of the mediastinum, the neck, pulmonary hilum, thyroid gland, lung, pleura, or pericardium [5-8].

The clinical features, diagnostic evaluation, and treatment of thymoma, including thymic carcinoma, are discussed separately. (See "Clinical presentation and management of thymoma and thymic carcinoma".)

Assessment of resection specimen

Gross appearance — Grossly, most thymomas are circumscribed, tan, firm masses (picture 1). They may range from microscopic lesions to tumors over 30 centimeters in diameter. The cut surface is often lobulated, with bands of fibrous stroma (picture 2). Cystic changes may be extensive, and in such cases, the cyst wall should be sampled carefully to search for tumor foci.

Thymomas can be encapsulated, invade the surrounding mediastinal adipose tissue with or without invasion of the mediastinal pleura, or extend beyond the mediastinal pleura into lungs, pericardium, heart, large vessels, and/or involve the phrenic nerves. They may also be found as implants along the pleura, pericardium, and/or diaphragm. The extent of invasion forms the basis of current tumor, node, metastasis staging. Good communication is necessary between surgeon and pathologist, which includes orientation of the specimen by the surgeon so that margins can be appropriately evaluated and any anatomic structure removed in addition to the thymus (eg, pericardium, mediastinal pleura, phrenic nerve, large vessels) can be adequately identified.

For precise staging, all regional lymph nodes need to be sampled from the thymectomy specimen. Separately submitted lymph nodes, appropriately site-identified, are also desirable.

Classification — The clinical relevance of the World Health Organization (WHO) classification system has been validated by many studies [9,10]. However, the prognostic significance may not apply to all subtypes, as some studies have shown a similar clinical outcome for type A and B1 and possibly B2 thymomas, while type B3 thymomas typically have a more adverse outcome [11]. Moreover, staging and possibly degree of resection (complete versus partial) are stronger prognostic parameters for thymomas [12]. (See 'Staging of thymic tumors' below and 'Prognostic implications' below.)

The WHO morphologic classification of thymomas is as follows (table 2):

●Type A thymomas account for 11.5 percent of all thymomas [13]. They are composed of bland spindle cells and possibly a few scattered lymphocytes (picture 3). Sixty percent of patients present at stage I [4]. Atypical type A thymomas are morphologically reminiscent of type A thymomas but show hypercellularity, increased mitotic activity, and/or necrosis [4]. In particular, necrosis appears to be correlated with advanced stage [14,15]; however, these findings still need to be validated. Similar findings can also rarely be seen in type AB thymomas.

●Type AB thymomas account for 25 percent of all thymomas [13]. They are a mixture of type A and type B1 or B2 thymoma (picture 4). A thymoma that is predominantly comprised of type A morphology but contains ≥10 percent area of terminal deoxynucleotidyl transferase (TdT)-positive lymphocytes should be classified as type AB thymoma. The components are either intermixed or distinct. Sixty-seven percent of patients present at stage I.

●Type B1 thymomas account for 17.5 percent of all thymomas [13]. They are predominantly comprised of lymphocytes with only scattered epithelial cells, typically not forming clusters or only clusters of two epithelial cells (picture 5). Type B1 thymomas contain paler medullary islands with or without Hassall corpuscle-like elements. Fifty percent of patients present at stage I.

●Type B2 thymomas account for 26 percent of all thymomas [13]. They contain more epithelial cells, often forming clusters of more than two epithelial cells (picture 6). Although unusual, medullary islands may be present. In addition, the cytologic atypia of the tumor cells in B2 thymomas can be more pronounced and may even show anaplastic features. Thirty-two percent of patients present at stage I.

●Type B3 thymomas account for 16 to 21 percent of all thymomas [13]. They are predominantly comprised of large, polygonal tumor cells that may show increased cytologic atypia and only a few or no scattered lymphocytes. Perivascular spaces are usually present (picture 7). These thymomas have a prognosis that is worse than that of other thymomas but better than thymic carcinomas, with only 19 percent of patients presenting at stage I [4,10].

Histologic heterogeneity is common, with more than one histologic subtype frequently present in one tumor. Therefore, subtyping of thymomas is not performed on biopsies (except for a diagnosis of carcinoma, as discussed below). (See 'Thymic carcinoma' below.)

In resection specimens, all histologic components of a thymoma should be reported in 10-percent increments, starting with the most prominent component (except for type AB thymomas, thymomas with carcinoma component [combined thymic carcinoma], and thymomas with carcinoid component [combined carcinoid]) [4]. In combined thymic carcinomas and carcinoids, the carcinoma or carcinoid component, respectively, should be mentioned first independent of the percentage of that component.

Histology — Thymomas are characterized by a lobulated architecture. Cellular lobules are comprised of various proportions of neoplastic epithelial cells and reactive thymocytes. The lobules are intersected by fibrous bands (picture 2). Many thymomas are at least partially surrounded by a fibrous capsule.

Thymomas are morphologically classified according to the WHO based on the shape of the epithelial tumor cells, the ratio of tumor cells to thymocytes, and the cytologic atypia of tumor cells (table 2). (See 'Classification' above.)

Growth patterns that can be particularly seen in type A and AB thymoma or micronodular thymoma with lymphoid stroma include microcystic changes, storiform growth, staghorn-shaped vessels resembling those seen in solitary fibrous tumors, rosettes similar to neuroendocrine tumors, gland-like structures, or a papillary growth pattern [4,16,17]. Prominent plasma cell infiltrates, microcystic patterns, and prominent myoid cells (rhabdomyomatous thymoma) may be encountered [18,19]. Dilated perivascular spaces can occur in type B1, B2, and B3 thymoma [17,20]. The spaces are filled by plasma fluid and may contain a few lymphocytes, plasma cells, or foamy macrophages (picture 7). Small vessels with hyalinized walls are often present in the center of these spaces. Neoplastic cells surrounding these spaces may show a palisading arrangement. Other histologic features seen in thymomas include Hassall corpuscles (specifically in type B1 (picture 5) but also some B2 thymomas) and a "starry-sky" pattern [20].

Sometimes the distinction between type B1 and B2 thymomas can be difficult. While both are lymphocyte-rich thymomas, type B1 thymomas contain areas of medullary differentiation (medullary islands) and only scattered epithelial cells without clustering (<3 contiguous epithelial cells), while type B2 thymomas contain more epithelial cells that frequently cluster (≥3 continuous epithelial cells) (picture 6) [17]. Type B1 thymomas can also be mistaken for small lymphocytic lymphomas, specifically on small biopsies. Recognition of a meshwork of epithelial cells can be facilitated by the use of a keratin stain (picture 8). Type B3 thymomas (picture 7) (and occasionally even type A or atypical A thymomas) may be confused with thymic carcinomas or squamous cell carcinoma metastatic from other sites. While thymomas have a preserved lobulated architecture, thymic carcinomas exhibit a distorted architecture with variably sized cell nests and possibly even single cells in a desmoplastic stromal reaction. Thymomas can show extensive cystic changes or may be associated with a thymic cyst (picture 9).

Molecular findings — Thymomas have an unusually low mutational burden for malignant tumors [21].

The most common mutations in thymic epithelial tumors (TET; thymomas and thymic carcinomas) include mutations in the following:

●General transcription factor II-i (GTF2I; 39 to 42 percent of cases)

•In TET, GTF2I mutations are missense mutations in codon L424H, which appears to be unique to TET [21]. However, the pathogenetic significance of that mutation of the gene is largely unknown. GTF2I mutations are most common in type A (82 to 100 percent) and AB thymomas (70 to 79 percent), followed by B1 (0 to 32 percent), B2 (0 to 22 percent), and B3 (10 to 21 percent) thymomas. They are only rarely found in thymic carcinomas (0 to 8 percent) [4,21,22]. In TET, GTF2I mutation has been identified as an independent favorable prognostic factor [22].

●Tumor protein p53 (TP53; 25 to 36 percent),

●KIT (6 to 20 percent of carcinomas), and

●Cyclin-dependent kinase inhibitor 2A (CDKN2A; 11 to 38 percent of thymic carcinomas, also in rare B3 thymomas)

●Various TETs may harbor mastermind-like transcriptional coactivator 2 (MAML2) rearrangements including a subset of thymic mucoepidermoid carcinomas, metaplastic thymomas (due to YAP1-MAML2 gene fusion), and a small subset of B2 and B3 thymomas (due to KMT2A-MAML2 gene fusion) [23-27].

●In a few cases, mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), cyclin D1 (CCND1), anaplastic lymphoma kinase (ALK), Ataxia-Telangiectasia mutated (ATM), avian erythroblastic leukemia viral oncogene homolog 4 (ERBB4), fibroblast growth factor receptor 3 (FGFR3), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and serine/threonine-protein kinase 11 (STK11) genes have been identified [21,22,28-32]. Furthermore, thymic hyalinizing clear cell carcinoma with EWS RNA-binding protein 1 (EWSR1) translocation has been described [33].

Immunohistochemistry — Thymic epithelial cells stain for epithelial markers such as keratins, epithelial membrane antigen, p63, p40, and usually paired box 8 (PAX8; polyclonal antibody) [34]. Thymic lymphocytes mark with TdT, cluster of differentiation (CD)1a, CD3, CD5, CD45, and CD99 [35,36]. In a subset of type A and AB thymomas, neoplastic epithelial cells also stain for CD20 and rarely thyroid transcription factor-1 (TTF-1) [37,38]. (See 'Classification' above.)

Differentiation between thymomas and thymic carcinomas is discussed below. (See 'Differential diagnosis' below.)

Prognostic implications — Although some multivariate analyses suggest that staging is the most important prognostic factor [12,39,40], the prognosis is probably multifactorial, with histologic features, staging, and completeness of resection contributing to the clinical behavior of these tumors [10,12,41-43]. This is discussed in more detail elsewhere. (See "Clinical presentation and management of thymoma and thymic carcinoma", section on 'Prognosis'.)

THYMIC CARCINOMA

Assessment of resection specimen

Gross appearance — Thymic carcinomas are commonly large, firm, infiltrating masses, with frequent areas of cystic change and necrosis [44]. These tumors are encapsulated in 15 percent of cases or less [45]. A mucoid cut surface is described in mucoepidermoid carcinomas [46]. Multilocular thymic cysts have been reported in association with mucoepidermoid carcinomas and basaloid carcinomas [46,47].

Classification — The World Health Organization morphologic classification of thymic carcinomas is included in the table (table 2).

Histology — Thymic carcinomas are cytologically malignant (picture 10) and may manifest cystic changes. While a certain amount of necrosis, atypia, and mitoses can be encountered in occasional thymomas, these findings are common in thymic carcinomas. An infiltrative growth pattern associated with desmoplastic stroma is often seen, without evidence of immature T lymphocytes. The lymphocytes exhibit the phenotype of mature T cells (terminal deoxynucleotidyl transferase [TdT] negative, cluster of differentiation [CD]1a negative, CD3 positive, and CD4 positive or CD8 positive). B cells and plasma cells are also seen.

Thymic carcinomas display a variety of histologic subtypes (table 3), emphasizing the ability of thymic epithelium to differentiate in a variety of directions:

●Squamous cell carcinoma – Squamous cell carcinomas are by far the most common thymic carcinomas. They morphologically resemble squamous cell carcinomas elsewhere (picture 10). They can be keratinizing or nonkeratinizing.

●Basaloid carcinoma – This tumor is composed of neoplastic basaloid cells that are characterized by a high nuclear-cytoplasmic ratio. The neoplastic cells grow in nests or line small cystic spaces. Peripheral palisading is a characteristic feature.

●Lymphoepithelial carcinoma – This tumor is composed of cytologically malignant, large, polygonal cells with prominent nucleoli that often grow in a syncytial pattern, in sheets and nests. A dense lymphoplasmacytic infiltrate is present and may obscure the tumor cells (picture 11 and picture 12). This carcinoma has the morphology of nasopharyngeal lymphoepithelial carcinoma, and Epstein-Barr virus has been implicated in its pathogenesis and can be identified at least in a subset of these cases (picture 13) [48,49]. Lymphoepithelial carcinoma is highly aggressive and associated with a poor prognosis [4]. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Epstein-Barr virus' and "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Histology'.)

●NUT carcinoma of the thorax – Nuclear protein of the testis (NUT) carcinomas are rare but very aggressive carcinomas. Fifty-one percent of patients have metastases at time of presentation, and the outcome is usually fatal with a median overall survival of 6.7 months. These tumors have a midline predominance (90 percent) and occur most commonly in the thorax (57 percent). There is no sex predilection, and the median age ranges between 16 and 50 years old (age range, 0.1 to 78 years). These tumors are considered an aggressive subset of squamous cell carcinoma [50-54]. A NUT immunostain shows a speckled nuclear expression pattern (picture 14 and picture 15) [55]; other immunostains are listed in the table (table 4). These tumors are characterized by rearrangement of the NUT gene (NUTM1) most commonly (70 percent of cases) and bromodomain-containing protein (BRD)4-NUT - t(15;19)(q14;p13.1); other rearrangements such as BRD3-NUT or NUT-variant fusions have also been identified [56].

●Clear cell carcinoma – This tumor is comprised of islands and trabeculae of neoplastic cells with clear cytoplasm [57] set in fibrous stroma; some show more extensive hyalinization around the tumor cell islands, similar to hyalinizing clear cell carcinomas of salivary glands and lung. In these tumors, EWS RNA-binding protein 1 (EWSR1) translocation has been identified and these tumors have been termed hyalinizing clear cell carcinoma [33]. While clear cell carcinomas are exceedingly rare, they are associated with a poor prognosis due to local recurrence or metastatic disease [58].

●Low-grade papillary adenocarcinoma of the thymus – These tumors are characterized by cuboidal or polygonal cells with only mild atypia, small nucleoli, and a small amount of cytoplasm growing in tubulopapillary pattern. Fibrovascular cores are identified in the papillary structures. These tumors may be associated with type A or AB thymomas [4].

●Mucoepidermoid carcinoma – Mucoepidermoid carcinomas are composed of intermediate cells (polygonal cells with eosinophilic cytoplasm, small round nuclei, and inconspicuous nucleoli), squamous cells, and mucin-producing (goblet) cells (picture 16). Mucoepidermoid carcinomas can be low or high grade [46]. Mastermind-like transcriptional coactivator 2 (MAML2) rearrangement is disease defining and has been shown in 50 to 56 percent of thymic mucoepidermoid carcinomas [25,26].

●Enteric-type adenocarcinoma of the thymus – This tumor morphologically and immunophenotypically mimics colorectal adenocarcinoma. It is characterized by a mucinous or tubulopapillary morphology (picture 17) or clusters of tumor cells floating in extracellular mucin. Intracytoplasmic mucin may also be seen. The tumor cells exhibit an enteric phenotype with expression of at least one of the markers cytokeratin (CK)20, CDX2, and mucin (MUC)2; expression of CK7 or CD5 may be present, while thyroid transcription factor 1 (TTF-1) and CD117 are negative [4].

●Adenocarcinoma, not otherwise specified – These carcinomas are characterized by glandular differentiation and/or intracytoplasmic mucin but do not exhibit features of low-grade papillary adenocarcinoma or enteric-type adenocarcinoma [4].

●Sarcomatoid carcinoma – Sarcomatoid carcinomas are composed in part or completely of spindled epithelial cells. When tumors show heterologous components such as rhabdomyoblastic or cartilaginous differentiation [59], they are classified as carcinosarcomas. The differential diagnosis of sarcomatoid carcinoma includes synovial sarcoma of the mediastinum [60]. Identification of t(X; 18)(p11.2;q11.2), SYT-SSX1, or SYT-SSX2 gene fusion or expression of SS18-SSX fusion antibodies can help confirm the diagnosis of synovial sarcoma [61].

●Undifferentiated carcinoma – Undifferentiated carcinoma is composed of sheets of undifferentiated cells, the epithelial nature of which should be documented by immunohistochemistry [4] (picture 18). Germ cell tumors and metastatic malignant melanoma should be excluded.

Molecular findings — The most common mutations in thymic epithelial tumors (thymomas and thymic carcinomas) are discussed above and summarized in an update from an expert group [62]. (See 'Molecular findings' above.)

Immunohistochemistry — Some stains may be useful in distinguishing thymic carcinoma from other entities (table 4). This is discussed in detail below. (See 'Differential diagnosis' below.)

Differential diagnosis — The differential diagnosis includes metastatic carcinoma to mediastinal lymph nodes. Because the morphology of thymic carcinoma is similar to features of these tumors elsewhere, their distinction from metastatic disease can be challenging. Ultimately, the distinction between thymic carcinoma and metastatic disease requires clinicoradiologic correlation and the clinical exclusion of metastatic disease [63,64].

Thymic carcinoma has a morphology and biology that is distinct from thymoma; nevertheless, differentiating a thymic carcinoma from a thymoma can be problematic.

●Clinically, thymic carcinoma is usually not associated with paraneoplastic syndromes.

●On histologic examination,

•Thymic carcinoma does not have an immature T lymphocytic component, although B lymphocytes, plasma cells, or mature T lymphocytes can be found within the stroma.

•The lobulated pattern of thymoma, separated by thick fibrous bands, is not found in thymic carcinoma, which displays a desmoplastic stroma. Moreover, histologic features characteristic of thymoma, such as perivascular spaces, medullary differentiation, and Hassall corpuscles, are not seen in thymic carcinomas.

•Carcinoma and thymoma may be found synchronously, or carcinoma may develop within a pre-existing thymoma [65]. These tumors are reported as combined carcinomas, and both the thymoma and the carcinoma components should be reported starting with the carcinoma component [4].

●Immunohistochemical findings include:

•Expression of cluster of differentiation (CD)5 and CD117 might be helpful to distinguish thymic carcinoma from thymoma, as these markers are only rarely expressed in thymomas but are expressed in the majority of thymic squamous cell carcinomas [38,66-68]. Furthermore, loss of expression of BRCA-associated protein-1 (BAP1) and/or mTAP indicates carcinoma and argues against thymoma [68]. Indeed, a panel of CD117 (expression in >10 percent of tumor cells), Tdt, BAP1, and mTAP has recently been suggested as useful in the distinction of thymic carcinoma from thymoma [68].

•A combination of CD5, CD117, and paired box 8 (PAX8, polyclonal) might be helpful specifically in the distinction of thymic squamous cell carcinomas (dual expression of CD5 and CD117 with or without PAX8) from pulmonary squamous cell carcinomas, although none of these stains appear specific to thymic carcinoma [64].

Prognostic implications — The histologic subtype of thymic carcinoma may have some prognostic significance with NUT carcinoma, lymphoepithelial carcinoma, sarcomatoid carcinoma, undifferentiated carcinoma, clear cell carcinoma, and poorly differentiated squamous cell carcinoma having in general a worse prognosis [4,44].

THYMIC NEUROENDOCRINE TUMORS — Twenty-five percent of thymic neuroendocrine tumors arise in the setting of multiple endocrine neoplasia, type 1 (MEN-1) syndrome [69]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

The histologic diagnosis is based upon recognition of neuroendocrine features such as organoid nests, trabeculae, rosettes, or palisading and homogeneous cytologic features with finely granular nuclear chromatin (picture 19 and picture 20 and picture 21).

Further details regarding the histology, clinical presentation, differential diagnosis, and treatment, are presented elsewhere. (See "Thymic neuroendocrine (carcinoid) tumors".)

STAGING OF THYMIC TUMORS — Thymomas, thymic carcinomas, and thymic neuroendocrine tumors are staged according to the tumor, node, metastasis staging of the American Joint Committee on Cancer/Union for International Cancer Control (table 5) [70]. Other staging systems, including the Masaoka staging system, are discussed elsewhere. (See "Clinical presentation and management of thymoma and thymic carcinoma", section on 'Staging'.)

GERM CELL TUMORS — Mediastinal germ cell tumors (GCTs) can occur as primary neoplasms in the mediastinum. Whether these tumors represent a malignant transformation of germ cells migrating along the midline during embryogenesis or originate from the primordial cells of the thymus with germ cell potential is still a subject of debate. The close association of mediastinal GCTs with the thymus and the presence of placental-like alkaline phosphatase (PLAP)-positive cells within the normal thymus support a potential thymic etiology [71,72].

The clinical manifestations, diagnosis, and treatment of extragonadal GCTs arising in the mediastinum are discussed separately. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum".)

Histologic subtypes — The histologic types of GCTs in the mediastinum are similar to those that occur in the testis and ovary (table 6) [73,74]. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis" and "Anatomy and pathology of testicular tumors".)

Mature teratoma — Mature teratomas are often cystic. They occur in all age groups but are most frequently seen in adolescents.

Grossly, mature teratomas are tan, soft, cystic structures measuring from 3 to 21 cm in greatest diameter (picture 22) [73]. Histologically, they are composed of adult-type tissue derived from the three embryonic layers (mesoderm, endoderm, and ectoderm (picture 23)). Mature teratomas are negative for 12p overrepresentation [75]. They should be distinguished from bronchogenic cysts (which are composed of respiratory epithelium), seromucinous glands, smooth muscle, and/or cartilage, which are all tissues that may be seen in large airways but lack other elements.

Immature teratomas — Macroscopically, immature teratomas form often cystic masses with areas of hemorrhage and necrosis. Histologically, they are characterized by mature elements from all three germ layers mixed with immature embryonic tissue (picture 24). While endodermal, ectodermal, and mesodermal tissues displaying various stages of maturation are found within these tumors, immature neuroectodermal elements predominate. This component consists of rosettes and neuroepithelium-forming tubules, some of which may even contain melanin pigment.

Evidence suggests that there are two possible distinct pathways to the development of teratomas in the mediastinum [76]:

●Benign teratomas that exhibit organoid growth, without cytologic atypia, and no 12p aberrations are thought to arise from benign precursor cells.

●Malignant teratomas that show cytologic atypia and often have increased chromosome 12p copy numbers are likely derived from malignantly transformed precursor cells. While benign teratomas can occur in children, females, and males, malignant teratomas are, in general, seen in postpubertal males.

Seminomas — Seminomas are found predominantly in postpubertal males (table 6) [77].

Grossly, mediastinal seminomas are large, solid, soft, and tan masses with a lobulated appearance on cut surface [78]. Histologically, seminomas have a characteristic nested pattern comprised of epithelioid tumor cells that are surrounded by a thin fibrovascular stroma, which frequently contains scattered lymphocytes (picture 25). The tumor cells have abundant cytoplasm, which is usually clear, and the nuclei have a vesicular chromatin pattern; nucleoli may be prominent. In the mediastinum, seminomas have some characteristic features (picture 25 and table 6) [74,78]. The differential diagnosis of seminomas includes thymoma and thymic cyst, nodular-sclerosing Hodgkin lymphoma, reactive lymphoid hyperplasia, and infection (granulomatous inflammation).

Approximately 8 to 20 percent of mediastinal seminomas can present as multiloculated, cystic masses up to 19 cm in diameter [79,80]. These tumors generally occur in asymptomatic young males and seem to be associated with a good prognosis [80]. Histologically, these cystic lesions consist of a multilocular thymic cyst lined by squamous or cuboidal epithelium with seminomatous tumor cells present in the wall of the cyst.

Immunohistochemical study of seminomas is summarized in the table (table 6) [81]. Beta-human chorionic gonadotropin (beta-hCG) is positive in 3 to 17 percent of cases, while alpha fetoprotein (AFP) is almost invariably negative. The D2-40 stain is also positive in extragonadal seminomas [82].

Nonseminomatous GCTs — Nonseminomatous germ cell tumors (GCTs) include yolk sac tumors, embryonal carcinomas, choriocarcinomas, and mixed GCTs.

●Yolk sac tumor – Yolk sac tumor primarily affects young males, but rare cases in females and children have been reported. Typically, serum AFP concentrations are elevated, although that is not entirely specific [83].

Grossly, yolk sac tumors are large, necrotic, and hemorrhagic masses that invade adjacent structures. Histologically, mediastinal yolk sac tumors can grow in many patterns (picture 26). Immunohistochemistry studies are summarized in the table (table 6). Beta-hCG is almost always negative [71].

●Embryonal carcinoma – Embryonal carcinoma is a rare, highly malignant neoplasm that seldom presents in a pure form [84]. Grossly, embryonal carcinoma often presents as a large, solid mass, with foci of hemorrhage and necrosis. It may invade adjacent structures. Morphologic features are noted in the table (table 6). Syncytiotrophoblastic giant cells are found scattered within the tumor.

Neoplastic cells in embryonal carcinoma are keratin positive (table 6). PLAP has a variable immunoreactivity, and AFP and beta-hCG are each typically positive in one-quarter to one-third of cases, respectively [71].

●Choriocarcinoma – Choriocarcinoma is a highly malignant GCT that mainly affects young males and is often found in association with other GCTs, particularly embryonal carcinoma. Gynecomastia and elevated serum beta-hCG are characteristic, and most patients present with intra- or extrathoracic metastasis at the time of diagnosis.

Grossly, choriocarcinoma is a large, soft, characteristically hemorrhagic and partially necrotic mass [85]. A biphasic cell population composed of cytotrophoblasts and syncytiotrophoblasts is characteristic (table 6). The former are mononuclear, round cells with clear cytoplasm, atypical nuclei, and prominent nucleoli, while the latter population consists of large, atypical, multinucleated giant cells found in clusters throughout the tumor and around hemorrhagic and necrotic lakes (picture 27).

Immunohistochemical staining reveals reactivity for keratin almost universally (table 6). Beta-hCG is always positive in the syncytiotrophoblastic component [71].

●Malignant mixed GCTs – Malignant mixed GCTs are composed of a combination of two or more histologic types of GCT [86]. The prognosis depends upon the histologic components of the tumor; thus, the pathology report should include the approximate percentage of each histologic type of GCT.

Somatic or hematologic malignancies can arise in GCTs. In fact, a sarcomatoid component is most frequently seen in primary mediastinal GCTs and is more commonly found in mature teratomas than immature teratomas, choriocarcinomas, yolk sac tumors, and seminomas. Rhabdomyosarcoma components are also more common than angiosarcoma, leiomyosarcoma, glioblastoma, malignant peripheral nerve sheath tumor, epithelioid hemangioendothelioma, or undifferentiated sarcoma components. It is important to diagnose such tumors as primary mediastinal GCTs with sarcomatoid component, as they are usually unresponsive to conventional chemotherapy and have a dismal prognosis. It is recommended to estimate the involved sarcomatous area. Primary mediastinal GCTs with sarcomatoid component have a worse prognosis than their gonadal counterpart. Only 18 percent of patients are alive at 12 to 42 months; 82 percent die from disease from 1 to 37 months [87].

These features can be difficult to discern on biopsies, and a high level of suspicion has to be maintained with a low threshold to perform GCT markers and chromosome 12p analysis. Chromosome 12p abnormalities are common in primary mediastinal GCT and in one study were found in 22 (of 23) mediastinal seminomas by fluorescence in-situ hybridization including amplification and i12p [88].

There is no official staging system of primary mediastinal GCT, although a proposed system has been published [4,74].

LYMPHOMA — A variety of lymphomas can present in the mediastinum, either alone or as a clinically significant component of more widespread disease. These tumors are discussed elsewhere and include:

●Hodgkin lymphoma (see "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults").

●Diffuse large B cell lymphoma (see "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma").

●Primary mediastinal large B cell lymphoma (see "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Primary mediastinal large B cell lymphoma').

●Lymphoblastic leukemia/lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma").

●Mucosa-associated lymphoid tissue lymphoma (see "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)").

MESENCHYMAL TUMORS — Either benign or malignant, mesenchymal tumors are rare mediastinal neoplasms (less than 2 percent (table 7)) [89,90]. The symptoms are identical to those of other mediastinal masses, and the pathologic features are similar to those of other tumors of soft tissue occurring at other sites. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

●Neurogenic tumors – Mediastinal neurogenic tumors represent 19 to 39 percent of all mediastinal tumors and develop from local peripheral nerves, sympathetic and parasympathetic ganglia, and embryonic remnants of the neural tube. They are most frequent in the paravertebral/posterior compartment of the mediastinum, where they can cause neurologic symptoms by compression [91].

●Schwannomas – A variety of benign and malignant tumors of peripheral nerve origin can occur in the mediastinum, among which schwannoma is the most common (table 7). Mediastinal schwannomas are benign neoplasms that originate from Schwann cells and affect patients of both sexes, predominantly in the third and fourth decades of life [91].

Mediastinal schwannomas are most often asymptomatic, but signs of nerve compression and paralysis, Pancoast syndrome, and Horner syndrome can occur. Computed tomography reveals a round, well-circumscribed mass located in the paravertebral region or intercostal spaces. Focal calcifications and cystic changes are frequent. A characteristic clinicoradiologic feature of these tumors is their extension through an intervertebral foramen, resulting in dumbbell-shaped tumors, and neurologic symptoms of spinal cord compression. (See "Superior pulmonary sulcus (Pancoast) tumors".)

Grossly, schwannomas are encapsulated, solid, soft, yellow-pink nodules, with the capsule attached to the epineurium of the nerve that gives rise to the neoplasm. Microscopically, they are composed of spindle cells with elongated nuclei, forming interlacing bundles with focal nuclear palisading (Verocay bodies (picture 28)). A combination of hypercellular (Antoni A pattern) and hypocellular (Antoni B pattern) areas is characteristic. Nuclear atypia (picture 29) and stromal sclerosis can be seen in older lesions ("ancient" schwannomas). Mitotic figures are rare. Immunohistochemical studies reveal a strongly positive reaction with S-100 protein.

Mediastinal schwannomas are cured by surgical resection. (See "Approach to the adult patient with a mediastinal mass", section on 'Surgical resection'.)

●Paragangliomas – Paragangliomas are rare mediastinal tumors that usually originate from sympathetic ganglia and commonly secrete catecholamines. Mediastinal paraganglioma are most commonly located beneath the aortic arch above the left atrium and adjacent to the ascending aorta and trachea [92]. Although many behave in a benign fashion, one-quarter of the patients have synchronous or metachronous metastases [92,93]. Over one-half of the tumors harbor pathogenic mutations, most commonly mutations in one of the serine dehydratase (SDH) genes including SDHB, SDHC, and SDHD, and most of the patients have the same SDH germline mutation. Pathogenic mutations in the alpha-thalassemia (ATRX), telomerase reverse transcriptase (TERT), or tumor protein p53 (TP53) genes have also been identified. These tumors can occur sporadically or as part of a hereditary syndrome including von Hippel-Lindau, multiple endocrine neoplasia, or succinate dehydrogenase mutation syndrome [94,95].

Paragangliomas are usually well defined and highly vascularized tumors that morphologically are composed of bland-appearing epithelioid cells forming "Zellballen" (picture 30). The neoplastic cells express neuroendocrine markers such as synaptophysin and chromogranin but lack staining with keratins. Sustentacular cells can be highlighted by S100 protein.

●Others – Other neurogenic tumors in the mediastinum include neurofibroma, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma.

THORACIC SMARCA4-DEFICIENT UNDIFFERENTIATED TUMOR — SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)-deficient undifferentiated tumors were introduced in the 2021 World Health Organization classification. While they can occur anywhere in the body, they are seen in the mediastinum. The median age of the patients is 59 years (range, 44 to 76 years) with a male predominance. The median survival has been reported to be approximately seven months [96].

●Histology – Morphologically and phenotypically they may present with sarcomatous or carcinomatous features. Some show at least focal rhabdoid morphology (picture 31) [97].

●Immunohistochemistry – Loss of SMARCA4 (BRG1) expression is diagnostic in these very aggressive tumors (picture 32) [96]. In SMARCA4-deficient undifferentiated tumors, cytokeratin expression may be present in rare neoplastic cells in 83 percent of the cases [97]. Rarely, thyroid transcription factor-1 (TTF-1) may also be expressed in a few tumor cells. Cluster of differentiation (CD)34, SRY-box transcription factor 2 (SOX2), and spalt-like transcription factor 4 (SALL4) are often expressed, while the tumors fail to express desmin, nuclear protein of the testis (NUT), and S100. SMARCB2 (BRM) expression is also lost in most of these cases, while expression of SMARCB1 (INI-1) is preserved.

SUMMARY

●Overview – Mediastinal tumors are among the most difficult lesions examined by the surgical pathologist. Interpretation of pathologic specimens from the mediastinum requires familiarity with a wide range of neoplasms and careful clinical correlation. If tumors originally treated by nonsurgical means do not respond as expected, additional biopsies, special studies, or consultations may be necessary to achieve the correct diagnosis. (See 'Introduction' above and "Approach to the adult patient with a mediastinal mass".)

●Examination of specimens – Although frozen sections may be used intraoperatively for diagnosis, nonfrozen tissue should always be submitted for routine analysis and potential molecular studies. (See 'Issues with examination of specimens' above.)

●Thymoma – Thymomas are malignant epithelial neoplasms arising in the thymus, commonly located in the prevascular mediastinum, though they may also occur in other locations. They are typically lobulated in architecture and have an unusually low mutational burden (picture 5 and picture 6 and picture 8 and picture 4 and picture 2 and picture 7). (See 'Thymoma' above.)

●Thymic carcinoma – Thymic carcinoma has a morphology and biology that are distinct from thymoma. It lacks the lobulated architecture of thymomas and is characterized by cytoarchitectural features of carcinoma similar to those seen in other organs (picture 10 and picture 18). The differential diagnosis includes metastatic carcinoma to mediastinal lymph nodes. (See 'Thymic carcinoma' above.)

●Thymic neuroendocrine tumors – Thymic neuroendocrine tumors are rare tumors, the histologic diagnosis of which is based upon recognition of neuroendocrine features such as organoid nests, trabeculae, rosettes, or palisading and homogeneous cytologic features with finely granular nuclear chromatin (picture 19 and picture 20 and picture 21). These tumors are associated with multiple endocrine neoplasia, type 1 (MEN1) in approximately 25 percent of cases. (See 'Thymic neuroendocrine tumors' above.)

●Germ cell tumors – Mediastinal germ cell tumors (GCTs) can occur as primary neoplasms in the mediastinum. The histologic subtypes are mature or immature teratomas, seminomas, and nonseminomatous GCTs (picture 24 and picture 25 and picture 33 and picture 22 and picture 23 and picture 26 and picture 27). (See 'Histologic subtypes' above.)

●Lymphoma – A variety of lymphomas can present in the mediastinum, either alone or as a clinically significant component of more widespread disease. (See 'Lymphoma' above.)

●Neurogenic tumors – Neurogenic tumors develop from mediastinal peripheral nerves, sympathetic and parasympathetic ganglia, and embryonic remnants of the neural tube (picture 28 and picture 29). They are most frequent in the paravertebral compartment of the mediastinum, where they can cause neurologic symptoms by compression. They include schwannomas and others. (See 'Mesenchymal tumors' above.)

●Mesenchymal tumors – Mesenchymal tumors are rare mediastinal neoplasms that may be either benign or malignant, with pathologic features that are similar to those of other tumors of soft tissue occurring at other sites. (See 'Thoracic SMARCA4-deficient undifferentiated tumor' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mojgan Devouassoux-Shisheboran, MD, and William D Travis, MD, who contributed to earlier versions of this topic review.