Fig. 6.1
Mature teratoma. A needle core biopsy shows skin with epidermis (a, arrow, b), and sebaceous glands. In another area (a, arrowhead, c), respiratory epithelium is present. These findings are consistent with a mature teratoma comprised of ectoderm (skin) and endoderm (respiratory system). Resection confirmed a mature cystic teratoma. Magnification, × 20 (a), × 100 (b), × 600 (c)
Cysts and sampled cyst linings can be a pitfall in the biopsy of a mediastinal mass as they not only occur in mature teratomas. They also can be seen in many other entities in the mediastinum including thymic cyst, seminoma, and bronchogenic cyst amongst others. Therefore, if a cyst lining is identified in a biopsy of a mediastinal lesion, a thorough morphologic examination of the cyst wall is important to exclude a GCT. The threshold for ancillary studies including immunostains and possibly isochromosome 12p [i(12p)] by fluorescence in situ hybridization (FISH) should be low. Bronchogenic cysts may closely mimic mature teratomas because they are comprised of respiratory (ciliated) epithelium, smooth muscle, and mature cartilage and/or seromucinous glands. In general, the presence of tracheobronchial structures and respiratory epithelium in the absence of enteric-type epithelium, immature elements, atypia, and tumor necrosis favors bronchogenic cyst [34]. Expression of CK7 by the epithelial cells in the absence of CDX2 expression further supports a bronchogenic cyst. In contrast, teratomas in general have a mixture of enteric and respiratory epithelium and the majority of the glands express CK7, CK20, CDX2, and TTF-1. In fact, coexpression of CDX2 and TTF-1 is only reported in teratomas [34]. However, as only limited material is present in small biopsies, a definite distinction between mature teratoma and bronchogenic cyst might not always be feasible and the possibility of an undersampled teratoma should be raised. In contrast to mature teratomas, thymic cysts harbor thymic tissue within the cyst wall and lack any heterologous elements. Recognizing Hassall corpuscles, the hallmark of thymic glandular tissue, helps to distinguish a thymic cyst from a cystic mature teratoma. In infants and children, meningoceles might present as paravertebral mediastinal cysts [35]. As meningoceles can show various amounts of neural tissue and calcification, they might be confused with teratomas. However, the clinical and radiographic features are usually characteristic of meningocele.
Mature teratomas can harbor malignant germ cell elements such as seminoma, embryonal carcinoma, or YST. They also can show morphologic features to suggest sarcomatous or carcinomatous transformation. In addition, teratomas might be associated with hematologic malignancies. As these tumors have a worse outcome it is crucial to recognize a malignant component in a lesion that otherwise shows elements of a mature teratoma (Fig. 6.2).
Fig. 6.2
Mature teratoma with component of immature teratoma, embryonal carcinoma and angiosarcoma. a A biopsy reveals a fibrotic, cellular (arrow) and necrotic neoplasm. Respiratory epithelium is identified (arrowhead, insert). b Cystic spaces are also lined by respiratory epithelium suggestive of mature teratoma. c High power view of the cellular area highlighted in figure a (arrow) shows nests of embryonal carcinoma as characterized by epithelioid cells with clear cytoplasm and large round to oval nuclei with prominent nucleoli. The neoplastic cells are positive for CD30 (c, insert), CAM 5.2 (d) and OCT4 and negative for PLAP and CD117 (not shown). e Immature cartilage is consistent with an immature teratoma component. f Large areas of the neoplasm are comprised of abnormal vascular channels lined by atypical spindle cells that mark with Factor VIII g, CD31 h, and CD34 (not shown), consistent with angiosarcoma. Magnification, × 20 (a), × 400 (a, insert, c, d), × 40 (b), × 200 (e–h)
Morphologic mimics of immature teratoma in the mediastinum include pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma amongst others [36–38]. Small biopsies might only contain a sarcomatous or blastomatous component and lack the more typical non-small cell carcinoma component that would help to distinguish these tumors from immature teratomas. Pulmonary blastoma might be the most difficult tumor to distinguish from an immature teratoma. This tumor occurs predominantly in adults and is composed of fetal-type adenocarcinoma and embryonic mesenchyme, both of which resemble fetal lung (Fig. 6.3) [39]. Fetal-type adenocarcinoma is characterized by glands or tubules that are lined by pseudostratified columnar, nonciliated epithelial cells with supranuclear or subnuclear vacuoles. Squamous morular metaplasia can occur and might result in an endometrioid appearance. The embryonic mesenchyme is characterized by condensation of spindle cells around the glands and might show heterologous differentiation which makes it even more difficult to distinguish from an immature teratoma. The fetal-type glands seen in pulmonary blastoma are most helpful to distinguish this tumor from an immature teratoma.
Fig. 6.3
Pulmonary blastoma. a A low power view of this biopsy reveals a glandular (upper right) and a stromal (lower left) component. b At high magnification the glands are lined by columnar epithelium with cells containing supranuclear vacuoles, features mimicking fetal adenocarcinoma. The glands are surrounded by spindle cells resembling the embryonic mesenchyme. Magnification, × 40 (a), × 400 (b)
Yolk Sac Tumors
YST are overall the second most common PMGCT. While they are the most common malignant PMGCT in patients less than 15 years of age [27], after puberty, YST are relatively less common, occur almost always in men and its incidence peaks in the third decade. Before puberty, metastases occur in 30% of mediastinal YST, most commonly to the lung, lymph nodes, liver, bone, and brain. After puberty, metastases occur in about half of patients, usually to the lung or intrathoracic lymph nodes; extrathoracic metastases are uncommon at that age.
As in the gonads, YST in the mediastinum can be comprised of a variety of morphologic patterns including microcystic (reticular), macrocystic, glandular–alveolar, endodermal sinus (pseudopapillary), myxomatous, hepatoid, enteric, polyvesicular, vitelline, solid and spindle cell pattern (Fig. 6.4). Usually, more than one pattern is identified. Schiller-Duval bodies are the hallmark of YST. Schiller-Duval bodies are comprised of a central blood vessel surrounded by tumor cells and a capsule that again is lined by an outer (parietal) rim of tumor cells. These structures are reminiscent of a glomerulus. However, they might not always be present in YST, and specifically small biopsies might lack Schiller-Duval bodies. Syncytiotrophoblasts can be admixed in an otherwise typical YST. Hematological malignancies (specifically acute leukemias and myelodysplastic syndrome) are commonly seen associated with mixed GCT with a yolk sac component (58%) but also in pure YST (25%).
Fig. 6.4
Yolk sac tumor. a A needle core biopsy reveals some glandular structures which are scattered throughout the biopsy (b–d). c Higher magnification shows a somewhat myxoid background. e Sheets of tumor cells comprise a solid component of the tumor. The neoplastic cells are positive for keratin AE1/AE3 (f), glypican 3 (g) and weakly AFP (h) and are negative for CD30 and PLAP (not shown). Magnification, × 20 (a), 100 (b, c, f), × 400 (d, e, g, h)
Seminoma
Seminomas usually occur in the prevascular mediastinum of men [9, 13, 24, 30, 40–43]. They are not found in prepubertal patients. The reported age ranges between 11 and 79 years with a mean age of 46.5 years in one study [43]; other studies report a peak in the third decade [24]. Seminomas can also become quite large with tumors described of over 16 cm in greatest diameter [9].
A few morphologic features appear to be unique in mediastinal seminomas including involvement of the thymus (Fig. 6.5), thymic epithelial cell hyperplasia, and cyst formation [44, 45]. In fact, prominent cystic changes have been described in 8% of mediastinal seminomas [45]. These tumors characteristically show areas of lymphoid hyperplasia, cysts lined by squamous epithelium, and cholesterol cleft granulomas. The lymphoid hyperplasia and the fact that the tumor cells might grow along the cyst wall makes the distinction of seminoma from thymic follicular hyperplasia or thymoma challenging. A high level of suspicion and low threshold for an OCT-4 stain is necessary to identify these tumors in a cystic lesion of the thymus. Non-necrotizing epithelioid granulomas might further obscure the tumor cells. Moreover, a granulomatous reaction, especially in a small biopsy, will present a pitfall as it might be misinterpreted as a possible infectious process. Mediastinal seminomas can also mimic thymomas, at least at low magnification on a small biopsy as the neoplastic cells can sometimes be arranged in cell nests that are separated by thin fibrovascular septa. In fact, fibrous septa/stroma have been described in 91% of seminoma [45]. The fibrovascular septa sometimes are infiltrated by a large number of lymphocytes. Cystic seminomas may histologically mimic multilocular thymic cysts [44].
Fig. 6.5
Seminoma. a A small biopsy is comprised of cellular areas (arrowhead) and fibrosis. b A high power view from the area highlighted by the arrowhead in figure a shows nests of large epithelioid cells characterized by clear and focally eosinophilic cytoplasm and round to oval nuclei with conspicuous nucleoli, morphologically suggestive of seminoma. c Non-necrotizing granulomas are also present. d Clusters of neoplastic cells similar to those in figure b are obscured by non-necrotizing granulomas. The neoplastic cells are positive for OCT4 (e) and CD117 (f) and show a peculiar dot-like staining pattern with keratin AE1/AE3 (g). h The keratin AE1/AE3 stain also highlights the background of benign thymic parenchyma. Magnification, × 20 (a, h), × 600 (b), × 200 (c, d), × 400 (e–g)
As elsewhere in the body, the tumor cells of mediastinal seminomas are in general characterized by clear cytoplasm, distinct cell border, and prominent nucleoli. Cellular pleomorphism and necrosis can occur. A few cases of anaplastic seminoma have been reported in the anterior mediastinum [46]. Rarely, intercellular edema and syncytiotrophoblasts have been described [9]. Mediastinal seminomas can be associated with another non-GCT component such as leiomyosarcoma but that is rare in that location [47].
Choriocarcinoma
Choriocarcinomas are also rare in the mediastinum, comprising only 3% of PMGCT. Almost all mediastinal choriocarcinomas have been reported in adult males (age range, 17–63). Choriocarcinomas are highly aggressive tumors with early hematogeneous dissemination. These tumors are characterized by a mixture of syncytiotrophoblasts and cytotrophoblasts with or without intermediate trophoblasts (Fig. 6.6). Syncytiotrophoblasts are large multinucleated cells with numerous, pleomorphic, dark-staining nuclei, variable number of nucleoli, and abundant dense eosinophilic or amphophilic cytoplasm [27]. These cells might contain cytoplasmic lacunae. Cytotrophoblasts are more uniform, polygonal cells with round nuclei, prominent nucleoli, and clear or eosinophilic cytoplasm. Atypical mitoses and cellular atypia are common. Intermediate trophoblasts might grow in sheets of mononuclear cells. Choriocarcinomas are typically intimately associated with dilated vascular sinusoids.
Fig. 6.6
Choriocarcinoma. a This biopsy is comprised of nests of neoplastic cells with central necrosis in a background of fibrosis. b The majority of the neoplastic cells are cytotrophoblastic and intermediate trophoblastic cells that are characteristically large and polygonal and have a single large round to oval nuclei with open nuclear chromatin and prominent nucleoli (c, arrowhead). c These cells are “capped” by syncytiotrophoblastic cells (arrow) that are comprised of dark-staining (in this case basophilic) cytoplasm and multiple nuclei. d Human placental lactogen mainly highlights the syncytiotrophoblastic cells. Magnification, × 40 (a), × 200 (b, d), × 400 (c)
Embryonal Carcinoma
Embryonal carcinomas are rare in the mediastinum and account only for up to 2% of PMGCT. It is predominantly a tumor of young men. Local tumor spread and hematogeneous metastases (lung, liver, brain, bones) are common; a quarter of patients have lung metastases at time of presentation. Lymphogeneous metastases are much rarer.
The morphologic features of mediastinal embryonal carcinoma are identical to their gonadal counterpart [27]. Tumor cells are characteristically large and polygonal or columnar and have indistinct cell borders. They grow in solid sheets, tubules, and/or papillary structures. Tumor cell nuclei usually have large single or multiple eosinophilic nucleoli. Mitotic activity is in general readily recognizable and tumor necrosis is common. Scattered single or small groups of syncytiotrophoblasts can occur in about one-third of cases.
Mixed Primary Mediastinal Germ Cell Tumors
As in the gonads, mixed PMGCT are comprised of at least two distinct types of GCT. In adults they account for 16% of all PMGCT, second only to teratomas and seminomas. Virtually, all patients are male. In children, most tumors are a combination of YST and teratoma (mature or immature). In adults, teratoma and embryonal carcinoma are the most common components; YST, seminoma, and choriocarcinoma are less common part of mixed PMGCT. While in adults the teratoma component is more often immature, in children, the teratoma component is more commonly mature. All components should be listed, however, not all components might be present in a biopsy. Adult mixed GCT are frequently associated with somatic malignancies.
Germ Cell Tumors with Somatic-Type Solid Malignancy
Sarcomatous differentiation of GCT is most frequently seen in the mediastinum. It may occur in association with mature teratomas or, less commonly, with other malignant PMGCTs including immature teratoma, choriocarcinoma, YST, and seminoma [48]. Rhabdomyosarcoma is the most common type of heterologous differentiation; angiosarcoma, leiomyosarcoma, glioblastoma multiforme, malignant peripheral nerve sheath tumor, epithelioid hemangioendothelioma and undifferentiated sarcoma might also occur [48]. Cases with components of chondrosarcoma, osteosarcoma, liposarcoma, malignant fibrous histiocytoma, primitive neuroectodermal tumor, and neuroblastoma have also been reported. Any somatic-type malignancy should be reported because PMGCT with sarcomatous differentiation do not respond to conventional GCT therapy and their prognosis is dismal [48]. Furthermore, patients with PMGCT with sarcomatous component appear to have a worse prognosis than their gonadal counterparts.
In a biopsy, maybe only a sarcomatous component is identified while the GCT per se is not present. If there is any clinical suspicion of an associated germ cell tumor, i(12p) might be helpful as sarcomatous components of GCT might harbor i(12p) [49].
Because of the poor prognosis of patients with PMGCT with sarcomatous component, its distinction from immature mesenchyme in an immature teratoma is critical. In general, the spindle cell component of immature teratomas is cytologically bland, relatively monomorphic and is typically condensed around teratomatous glands with a concentric, swirling growth pattern. In contrast, sarcomatous differentiation usually shows a higher architectural complexity with storiform growth pattern and intersecting fascicles infiltrating into surrounding tissues. Components of sarcomatous differentiation also commonly have more nuclear pleomorphism and hyperchromasia, obvious mitotic activity, obvious malignant heterologous differentiation, and lack intimately admixed glands. In addition, sarcomatous differentiation shows independent growth replacing teratomatous glands or other germ cell elements [50].
Ancillary Studies
Ancillary studies might be utilized to diagnose and type PMGCT and to distinguish them from other mediastinal tumors. Immunohistochemical and cytogenetic studies or karyotyping are most helpful. Serum markers might also be suggestive of certain GCT. However, while the immunophenotype and cytogenetic abnormalities of PMGCT are similar or even identical to their gonadal counterparts, some unique antigen expression patterns can be seen in PMGCT. Moreover, the expression of some antigens on PMGCT can harbor a pitfall as similar expression patterns might occur in mediastinal tumors that are in the differential diagnosis. Therefore, the threshold for ordering additional immunostains and/or cytogenetic studies should be low in the workup of a mediastinal tumor.
Immunohistochemical Studies (Table 6.1)
OCT-4 is an excellent immunostain to distinguish PMGCT such as seminoma and embryonal carcinoma from carcinomas in the mediastinum. 91–100% of seminomas and nearly 100% of embryonal carcinomas show nuclear reactivity with OCT3/4, and the specificity seems superior to other available markers [45, 51–55].
Table 6.1
Immunophenotype of primary mediastinal germ cell tumors and their mimickers [Frequency (% positive cases)]
Immunostain | Seminoma | Embryonal carcinoma | Yolk sac tumor | Teratoma | Choriocarcinoma | Lung adenocarcinoma | Small cell carcinoma | Thymic carcinoma |
|---|---|---|---|---|---|---|---|---|
100 | 100 | 0 | 0 | 0 | N/Aa | N/A | 0 | |
91-100 | 82–100 | 38 | 0 | 0 | 0 | N/A | N/A | |
75–100 | 77–100 | 30–59 | 43 | 0 | 17 | 82 | 80–86 | |
100 | 97 | 100 | 29 | 0 | 6 | 19 | 0 | |
0 | 0 | 56–100 | N/A | 0 | 60b | N/A | N/A | |
3 | 33 | 0 | 10–60 | 100 | 7–60 | 0 | 0 | |
43–100 | 59 | 40 | 0 | 0 | 25–67 | N/A | 0 | |
0 | 7 | 100 | 34 (immature) | 100 | 3 | N/A | N/A | |
48–88 | 100 | 100 | 100 | 100 | 100 | 100 | 100c | |
0–43 | 100 | 100 | 100 | 100 | 100 | 50–100 | 100 | |
0–39 | 0 | N/A | N/A | N/A | 25–82 | 0 | 100d | |
2–9 | 33 | 29 | 100e | 54 | 95–100 | N/A | 100 | |
0–2 | 73–100 | 0–11 | 40f | 0 | 0 | 0 | N/A | |
0 | 0 | 0 | 50 | N/A | 57–89 | 85–95 | 0 |
Keratin has been shown to be expressed in up to 43–88% of mediastinal seminomas, potentially leading to a misdiagnosis of carcinoma [43, 45, 50, 51, 56]. However, in most cases, keratin highlights only a small proportion of tumor cells with variable intensities [45]. CAM5.2 expression shows a rather strong dot-like paranuclear staining pattern in primary mediastinal seminomas [51, 56].
Strong membranous CD117 (kit) immunoreactivity has been reported in 75–100% of seminomas [57, 58]. However, in the mediastinum, CD117 is not specific to seminomas because it is also expressed in non-germ cell tumors including thymic carcinomas [59, 60], small cell carcinoma and adenocarcinomas of the lung [61]. In addition, embryonal carcinoma, YST, and choriocarcinoma may show some degree of weak CD117 reactivity.
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