In general, the immunophenotype of PMGCT is similar to its gonadal counter. However, there are some significant differences in the expression of some antigens, especially on tumor cells of seminomas [78]. For instance, in a study by Suster et al. [78], the low molecular weight keratin CAM 5.2, which shows a strong dot-like paranuclear staining pattern in seminomas, is expressed in 80 % of mediastinal seminomas but only in 20 % of testicular seminomas. Similarly, PLAP is expressed in 92.5 % of mediastinal seminomas (Fig. 8.3) but only in 50 % of testicular seminomas.

OCT4 has a high sensitivity and specificity for seminoma and embryonal carcinoma [79–81]. Nearly 100 % of seminomas and embryonal carcinomas show nuclear reactivity with OCT4, and the specificity seems superior to other available markers (Fig. 8.2f) [79–81].

Keratins can be expressed in 39–80 % of mediastinal seminomas and therefore might present a pitfall mimicking carcinoma [51, 77, 78]. However, in most cases, the epithelial markers highlight only a small proportion of tumor cells with variable intensities [73].

Strong membranous CD117 (kit) immunoreactivity has been reported in 75–100 % of seminomas (Figs. 8.2g and 8.3d) [82]. However, in the mediastinum, CD117 is not specific to seminomas because it is also expressed in other non-germ cell tumors including small cell carcinoma and adenocarcinomas of the lung [83] and thymic carcinomas [84, 85]. In addition, embryonal carcinoma, yolk sac tumor, and choriocarcinoma may show some degree of weak CD117 reactivity (Fig. 8.5e).

CD30 is expressed in over 80 % of embryonal carcinomas. However, CD30 is also expressed in various hematopoietic malignancies which commonly occur in the mediastinum such as mediastinal large B-cell lymphoma or Hodgkin lymphoma (Fig. 8.7) [86] but also occasionally in yolk sac tumors and rarely seminoma [78].

AFP is not a reliable marker for yolk sac tumors because of its low sensitivity [87]. Furthermore, AFP can be expressed in 60 % of hepatoid adenocarcinomas of the lung [88]. Serum evaluation of AFP and [beta]-human chorionic gonadotropin (beta-HCG) is frequently more sensitive than immunohistochemistry. However, beta-HCG is also not entirely specific to GCT and can be seen in 10–60 % of adenocarcinomas of the lung [89, 90].

Although placental-like alkaline phosphatase (PLAP) has traditionally been the marker of choice for GCTs (mostly seminoma), in the setting of an “undifferentiated” neoplasm in the mediastinum, its lack of sensitivity, generally high background staining, and the development of newer antibodies have rendered this stain less useful in current diagnostic practice.

Bosl et al. [11] found that the isochromosome of chromosome 12 [i(12p)] as evaluated by FISH studies is a useful marker for GCT in males. This was further confirmed in a study by Sung et al. [73] that showed abnormalities of chromosome 12p including 12p amplification and i(12p) in 22 out of 23 cases of mediastinal seminoma. Chaganti et al. [59] performed karyotypic analysis of 13 PMGCT and observed characteristic i(12p) in 69 % cases (9/13).

Although rare, testicular GCT can metastasize to the mediastinum [91]. However, in most mediastinal GCTs, examination of the testes fails to reveal a primary tumor. For instance, in 16 patients with extragonadal GCTs, the testicles did not have any palpable lesion [92]. However, occult testicular tumors were later identified in 10 of 12 patients with retroperitoneal GCT but in none of the mediastinal GCT. Therefore, not all testicular GCTs can be identified by palpation alone. In a study of 20 autopsy cases of mediastinal GCT, Luna and Valenzuela-Tamaris [93] identified only two cases in which the testes contained either an occult tumor or a well-defined testicular scar. Moreover, of 78 autopsies of patients with testicular GCTs, no autopsy showed solely metastases in the anterior mediastinum without involvement of other mediastinal lymph nodes (middle/posterior) [94]. In another such study of 220 cases of metastasizing testicular tumors, no metastases were documented in the mediastinum [95]. These studies emphasize that testicular GCT can metastasize to the mediastinum, but that appears to be rather exceptional, and GCTs in the mediastinum are usually of primary origin. However, the possibility of mediastinal GCT of testicular origin exists and must be excluded. A careful review of the past medical history, physical examination, and imaging studies are necessary to distinguish between primary and metastatic disease. Moreover, retroperitoneal tumor metastases are virtually always present in cases of testicular seminoma that have metastasized to the mediastinum.

Thymic cysts may be unilocular or multilocular and can potentially mimic teratoma or seminoma. The unilocular cysts, remnants of the third branchial pouch-derived thymopharyngeal duct, may be lined by cuboidal, columnar, or sometimes squamous epithelium and contain thymic tissue within the cyst wall (Fig. 8.8) [96]. Multilocular cysts are acquired cystic ductular dilatations due to inflammatory reaction of the thymic parenchyma and are frequently lined by squamous epithelium, but cuboidal or ciliated columnar linings are also described [97, 98]. Cholesterol granulomas and chronic inflammatory infiltrate are commonly found in the cyst wall of multiloculated thymic cysts. The lack of heterologous elements and the presence of thymic tissue underlying the epithelium should aid in the distinction from teratoma. However, seminoma and yolk sac tumors should be carefully excluded because these tumors can show similar cystic changes in the thymus as seen in a multiloculated thymic cyst [50]. Awareness of this secondary thymic change and thorough sampling are critical in excluding an associated GCT.

Enteric cysts are usually found in children and adolescents and are almost exclusively located in the posterior mediastinum (paraesophageal and gastroesophageal) [99–101]. The cyst wall contains a double layer of smooth muscle and can be lined by simple or pseudostratified columnar, squamous, or gastric mucosa.

Bronchogenic cysts, congenital anomalies of foregut origin, can be found in any mediastinal compartment and in any age group [101, 102]. They may closely mimic mature teratomas because they are comprised of respiratory epithelium, smooth muscle, and mature cartilage or mucous glands. Cysts with well or moderate architectural differentiation toward normal tracheobronchial structures, presence of respiratory-type epithelium, lack of enteric-type epithelium, immature elements, atypia, and tumor necrosis favor bronchogenic cyst [103]. The presence of CK7 expression in the absence of staining with CDX2 further supports bronchogenic cyst. In contrast, teratomas have a mixed enteric and respiratory epithelium, and the majority of the glands express CK7, CK20, CDX2, and TTF-1. Moreover, coexpression of CDX2 and TTF-1 was only found in teratoma [103].

Meningoceles are posterior mediastinal cysts which communicate with meninges. In general they occur in infants and children [104]. The clinical/radiographic features are usually characteristic. Microscopically, they might show various amounts of neural tissue and calcification and should not be confused with teratoma.

In children, pleuropulmonary blastoma (PPB) can potentially mimic a GCT because of its biphasic appearance and heterologous mesenchymal differentiation [105, 106]. It can be cystic and/or solid and has sarcomatoid characteristics. It is usually found in the lung but occasionally can be identified in the pleura. The cysts are typically lined by respiratory or cuboidal epithelium and lack the squamous, gastrointestinal, or neuroglial lining often seen in teratoma (Fig. 8.9). The primitive spindled cells of PPB often resemble embryonal rhabdomyosarcoma or fibrosarcoma, patterns which are unusual in teratoma but might be present as sarcomatoid component in other GCTs. Heterologous elements such as cartilage may rarely be seen in PPB. The cyst lining together with the absence of other organized elements helps to distinguish this rare malignant tumor from a primary intrapulmonary teratoma.

Sarcomatoid carcinomas of the lung are a broad spectrum of poorly differentiated non-small cell carcinomas that contain a sarcoma or sarcoma-like component (Fig. 8.10) [107]. The closest mimics of immature teratoma include pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma. Pleomorphic carcinoma contains a component of morphologically typical non-small cell carcinoma (i.e., squamous cell carcinoma, adenocarcinoma, or large cell carcinoma) admixed with a malignant spindle cell component lacking a specific line of heterologous differentiation. The obvious non-small cell lung carcinoma component should allow distinction from immature teratoma or PMGCT with sarcomatoid component in most cases. Carcinosarcoma, like pleomorphic sarcoma, is comprised of non-small cell carcinoma, but, in contrast to pleomorphic sarcoma, also contains a differentiated sarcomatous component (e.g., chondrosarcoma, rhabdomyosarcoma, osteosarcoma) (Fig. 8.11) [77]. Again, the presence of typical non-small cell lung carcinoma should allow the distinction in most cases. The closest histologic mimic of teratoma is the pulmonary blastoma [108–110]. Despite the name, this is a tumor predominantly of adults characterized by an admixture of fetal-type adenocarcinoma (tubules lined by pseudostratified columnar, nonciliated epithelium with clear to lightly eosinophilic cytoplasm) and embryonic mesenchyme, both of which resemble fetal lung between 10 and 16 weeks of gestation [111]. The glands often have supranuclear or subnuclear vacuoles and sometimes show squamous morular metaplasia creating an endometrioid appearance. The condensation of the spindle cell component around the glands may closely mimic immature teratoma, especially if heterologous differentiation is present. Recognition of the typical fetal-type gland morphology is key to this distinction.