Teratomas and Other Germ Cell Tumors of the Mediastinum Workup

Beta human chorionic gonadotropin

• Elevated levels of beta human chorionic gonadotropin (bhCG) virtually always are found in association with nonseminomatous germ cell tumors. Always obtain this study, as well as alpha-fetoprotein (AFP) levels, in young male patients presenting with an anterior mediastinal mass. Serum levels of bhCG greater than 500 mg/mL are said to be diagnostic for the presence of a nonseminomatous germ cell tumor.
• Seminomas generally do not produce elevated levels of this substance. Less than 10% of patients with seminoma have an elevated bhCG level, and the measured level is usually much lower than that found with nonseminomatous tumors.

Alpha-fetoprotein

• AFP almost always is elevated in individuals with nonseminomatous germ cell tumors. As noted above, always obtain this test in young males found to have an anterior mediastinal mass. As with bhCG, serum levels greater that 500 mg/mL are virtually diagnostic for nonseminomatous germ cell tumors.
• Elevation of the AFP level is not found in individuals with pure seminoma.

Tumor rejection antigen 1 (TRA-1-60) is a relatively new tumor marker for embryonal cell carcinoma. This study may be useful in monitoring patients with mediastinal germ cell tumors with an embryonal cell component.

CD30 is believed to be useful in the monitoring of patients with embryonal cell carcinoma as well.

Genetic analysis should be performed to determine the presence of chromosomal abnormality isochromosome 12p.

Chest radiography (see images below)

• Posteroanterior (PA) and lateral radiograph of the chest for an unrelated cause are the usual ways in which an asymptomatic mediastinal mass is identified. Chest radiography obviously is the first study that would be performed in an individual with symptoms referable to the thorax. The PA view allows for determination of bilaterality and superior or inferior location, while the lateral chest radiograph determines the specific compartment. A 25-year-old man is found to have an asymptomatic anterior mediastinal mass on a routine chest radiograph. This posteroanterior (PA) view shows the edges of the mass extending beyond the normal heart border. At surgery, the mass was found to be a benign teratoma. Later chest radiograph (see previous image) of a 25-year-old man with an asymptomatic anterior mediastinal mass. The arrow indicates the area the mass occupies in the anterior mediastinum. This was found to be a benign teratoma.
• The lateral chest radiograph is very helpful in the determination of the involved compartment of the mediastinum. This information, combined with the age, sex, and associated clinical findings, aids the physician in the proper choice of subsequent diagnostic studies.

CT scan of the chest and mediastinum

• CT has become a routine part of the diagnostic evaluation of mediastinal tumors, cysts, and other masses.
• CT is the test of choice for mediastinal masses. This test can greatly assist in determining the exact location of the mediastinal tumor and its relationship to adjacent structures. It also is useful in differentiating masses that originate in the mediastinum from those that encroach upon the mediastinum from the lung or other structures. It also detects pulmonary and mediastinal metastasis and differentiates from mediastinal fatty masses.
• The CT scan is very useful in differentiating tissue densities. This assists greatly in distinguishing structures that are cystic or vascular from those that are solid.
• CT scanning can reveal evidence of local invasion of adjacent structures by a mass or the presence of intrathoracic metastases.

Magnetic resonance imaging

• MRI is not routinely used to investigate germ cell neoplasms. MRI is more useful than CT to determine mediastinal invasion and involvement of the brachial plexus, diaphragm, or neural foramen, but this information is rarely useful from a clinical perspective.
• MRI offers direct multiplanar imaging. It can be used when iodinated contrast cannot be administered. It provides increased detail in the subcarinal and aortopulmonary window areas, as well as the inferior aspects of the mediastinum at the level of the diaphragm.
• MRI is more useful than the CT scan in the evaluation of invasion or extension of tumors, especially tumors closely associated with the heart. MRI is superior to the CT scan for the evaluation of masses located at the thoracic inlet or at the thoracoabdominal level. CT is superior in detecting pulmonary metastasis, spacial relationship to other mediastinal structures, and bony destruction.

Radionuclide scanning

• Nuclear imaging can be used selectively in the workup of mediastinal masses when specific tumors are suspected. The iodine-131 (I-131) or iodine-123 (I-123) scans are not indicated specifically for the identification of germ cell tumors, but they are used to identify thyroid tissue. They are mentioned here as a tool that can be used to distinguish the nature of an unknown anterior mediastinal mass.
• Because germ cell tumors and abnormalities of the thyroid (eg, ectopic thyroid, substernal extension of cervical thyroid) both present as anterior mediastinal masses, these iodine-tagged radionuclear studies may help to confirm or eliminate thyroid tissue as the diagnosis. These scans especially are useful in the identification of anterior mediastinal masses located at the level of the thoracic inlet, such as the substernal extension of a cervical thyroid goiter.
• Note that these studies must be performed before any tests requiring the administration of iodinated contrast because this material may interfere with thyroid uptake and scanning.

Echocardiography and ultrasonography

• Ultrasonographic methods have been used to differentiate solid from cystic mediastinal masses and to assist in determining a connection between a mass and adjacent structures. These studies are more useful in the evaluation of masses associated with the heart and in vascular abnormalities.
• In general, given the accuracy and detail provided by CT scan, MRI, and selected radionuclide scans, ultrasound techniques generally are not used as primary tools in the evaluation of mediastinal tumors and cysts.

Positron emission tomography

• Positron emission tomography (PET) has been studied extensively for the evaluation of a number of neoplasms, such as lung, colorectal, breast, lymphoma, and melanoma.
• Its use in the evaluation of mediastinal tumors is being evaluated. It has been reported to be useful with thymic neuroendocrine tumors.

Arteriography

• Conventional angiography has been used to differentiate mediastinal masses from vascular abnormalities, as well as to exhibit the relationship between known masses and adjacent vascular structures.
• MRI and magnetic resonance arteriography (MRA) appear to provide satisfactory definition of the masses in this area.

Transthoracic needle biopsy

• In the past, percutaneous biopsy methods were believed too dangerous to use in the evaluation of mediastinal masses, and open surgical biopsy was the diagnostic procedure of choice.
• Although still controversial, CT-guided fine-needle aspiration (FNA) and core needle biopsy techniques increasingly are used with success at several centers.^{[1, 2]} Differentiation of thymomas, lymphomas, and germ cell tumors can be made in a number of cases when tissue obtained from a core needle biopsy is subjected to special histologic staining methods, including immunohistochemical techniques. In some cases, lymphoma subtypes can be identified as well.
• Note that expert clinical judgment is necessary in selecting appropriate cases for this diagnostic method. In addition, considerable expertise in tissue processing and analysis is necessary for diagnostic accuracy, which is reported to be 85-95%. Often, open biopsy may be indicated to determine the specific germ cell tumor.
• FNA has been used occasionally for diagnosis of primary bronchogenic cysts. However, most authorities do not recommend aspiration of a cyst because a sample of the cyst wall, which is required for diagnosis, is not obtained by this method. Also, most cysts will recur after simple aspiration. This technique is not recommended for esophageal cysts. FNA has been described for neurogenic tumors, although because surgical resection is the treatment for these lesions after adequate workup, needle biopsy may be deemed an unnecessary step.

Cervical mediastinoscopy and substernal extended mediastinoscopy

• Cervical mediastinoscopy is a commonly used surgical diagnostic procedure for evaluation of the retrovascular pretracheal area of the mediastinum. This procedure is used most commonly for staging of bronchogenic carcinoma and for evaluation of hilar and paratracheal lymphadenopathy, but it can be modified into what has been termed a substernal extended mediastinoscopy to evaluate the prevascular area of the mediastinum.
• Thymic masses and any tumors found in the anterior mediastinum (eg, germ cell tumors), as well as lymph nodes of the aortopulmonary window, are accessible for obtaining a biopsy using this approach.

Anterior mediastinotomy

• This parasternal approach to the mediastinum has been used most commonly in situations in which standard cervical mediastinoscopy was believed or found to be inadequate.
• It classically is performed in the upper left parasternal area for access to the aortopulmonary window and areas of the anterior mediastinum inferior to the aortic arch.
• Anterior mediastinotomy is being replaced in many centers either by extended cervical mediastinoscopy or by video-assisted thoracic surgical (VATS) techniques.^[3]

Video-assisted thoracoscopy

• VATS techniques have been used successfully for biopsy of various mediastinal masses and are used commonly for the sampling of perihilar lymph nodes.
• VATS is one of the commonly used methods for evaluation of mediastinal lymphoma, but its use also has been extended to the anterior compartment of the mediastinum for biopsy and even resection of some masses.

Sternotomy and thoracotomy

• In spite of the numerous minimally invasive options available for histologic diagnosis of mediastinal tumors and cysts, open surgical access is needed at times.
• In some cases, standard sternotomy or thoracotomy may be the safest method available to obtain an adequate tissue diagnosis. Additional surgical exposures include the hemiclamshell thoracotomy with or without neck extension, clamshell, and, hemiclamshell with supraclavicular extension.
• Some surgeons perform a partial upper sternotomy, in which only the superior portion of a typical sternotomy is performed. It is viewed as an alternative and less invasive technique that is safe and effective for accessing the anterosuperior mediastinum.^[4]

Seminoma

Mediastinal seminoma has an appearance very similar to the type of seminoma that originates within the gonad. These tumors often possess some cystic changes and are associated with prominent reactive lymphoid follicular hyperplasia, granulomatous reaction, and fibrosis. The cellular portion of seminomas is comprised of sheets or lobules of medium-sized round or polygonal cells with clear cytoplasm separated by fine septae. Cellular areas often are infiltrated by lymphocytes. Individual cells have hyperchromatic nucleoli. Mitoses commonly are noted.

Teratoma

Teratomas often are divided into mature, immature, and teratoma with malignant components. Mature teratomas commonly are cystic and possess well-differentiated tissues from the 3 germinal cell layers. They often include cartilage or adipose tissue, glandular epithelium, and squamous epithelium.

Immature teratomas are less common and contain some mature epithelial and connective tissue components as well as immature areas with neuroectodermal and mesenchymal elements. Most of these tumors are well circumscribed by a wall of fibrous tissue, which may have some calcification within it. Cyst contents may include hair and sebaceous material.

Teratomas with additional malignant components have been classified additionally by the type of malignant tissue identified. These include (1) germ cell tumor type, (2) adenocarcinoma or squamous carcinoma, (3) mesenchymal or sarcomatous type, and (4) a combination of any of the previous 3 types.

Choriocarcinoma

Choriocarcinomas are composed of large pleomorphic multinucleated cells with ample eosinophilic cytoplasm known as syncytiocytotrophoblasts and cytotrophoblasts, which are polygonal cells with a clear cytoplasm, round nuclei, and conspicuous nucleoli. Most of these tumors are found to have large amounts of hemorrhage and necrosis.

Embryonal carcinoma

The architecture of embryonal carcinoma varies from solid to trabecular. The cells are highly atypical and have a moderate amount of cytoplasm, large nuclei, conspicuous nucleoli, and numerous mitotic figures. Histologic architecture can vary greatly within a single specimen from very primitive, undifferentiated cells to an organized, glandular configuration.

Yolk sac or endodermal sinus tumors

Yolk sac or endodermal sinus tumors have the most variable histology and include (1) the endodermal sinus type, which has a labyrinthine or festoon pattern and contains Schiller-Duval bodies; (2) glandular-alveolar; (3) microcystic; (4) myxomatous; (5) papillary; (6) polyvesicular-vitelline; (7) hepatoid; (8) solid; (9) clear-cell; (10) endometrioid; (11) parietal; (12) sarcomatoid; (13) macrocystic; and (14) intestinal, which manifest a pattern with villouslike projections lined by tumor cells.

The most common type identified in some large series is the reticular type, which has strands or cords of cells within a myxoid matrix. Schiller-Duval bodies, which are glomeruloid in appearance, as well as intracellular and extracellular hyaline globules, often are observed. Several of these histologic patterns can be found within the same tumor.

Well-established staging systems exist for several tumors that occur within the mediastinum. Most noted are those for thymoma, lymphoma, and neuroblastoma. These are listed below.

A well-defined staging system exists for germ cell tumors arising in gonadal structures; however, because of their infrequency, no specific staging systems have yet been described for primary germ cell tumors of the mediastinum. The staging system for germ cell tumors of the gonads, both seminomatous and nonseminomatous, is determined by the primary tumor, regional lymph node, remote metastases (TNM) classifications, as well as an additional category, S, signifying the serum tumor marker status of the individual. This staging system is provided below.

Masaoka postsurgical staging system for thymomas

Stage I: Grossly, the tumor is completely encapsulated. Microscopically, no invasion of the capsule is observed.

Stage II

• IIA: Grossly, invasion is observed into the surrounding fatty tissues or mediastinal pleura.
• IIB: Microscopically, tumor invasion is observed extending into the capsule.

Stage III: Gross evidence of invasion into an adjacent organ or structure (eg, pericardium, lung, great vessels [including vena cava]) is present.

Stage IV

• IVA: Tumor dissemination is observed in pleura or pericardium.
• IVB: Evidence of hematogenous or lymphogenous metastases is present.

Marino/Muller-Hermelink staging system

The other staging method, put forth by Marino and Muller-Hermelink, is based upon the cell type found within a given thymoma. Thymomas are classified as either cortical, medullary, or mixed. Some combination of these systems most likely may be the most accurate method of staging.

Ann Arbor staging system

Lymphomas found in the mediastinum are staged according to the Ann Arbor staging system.

• Stage I - Involvement of 1 lymph node region on either side of the diaphragm
• Stage II - Involvement of 2 or more lymph node regions on the same side of the diaphragm
• Stage III - Involvement of 2 or more lymph node regions on both sides of the diaphragm
• Stage IV - Disseminated organ involvement

INSS staging system

The International Neuroblastoma Staging System (INSS) is used widely for the staging of neuroblastoma and essentially has replaced other staging systems. The staging system for neuroblastomas is as follows:

• Stage I: Tumor is localized and confined to its area of origin. Complete gross excision can be performed (residual microscopic disease may or may not be present). Ipsilateral and contralateral lymph nodes removed at surgery are microscopically negative.
• Stage 2A: Incomplete gross excision of unilateral tumor occurs. Ipsilateral and contralateral lymph nodes removed at surgery are microscopically negative.
• Stage 2B: Complete or incomplete gross excision of a unilateral tumor with positive ipsilateral lymph nodes occurs. Identifiable contralateral lymph nodes are microscopically negative.
• Stage 3: Tumor is found to infiltrate across the midline with or without regional lymph node involvement or the tumor is unilateral (but contralateral lymph node involvement is found) or the tumor is midline with bilateral lymph node involvement.
• Stage 4: Tumor dissemination to bone, bone marrow, distant lymph nodes, liver, and other organs (except as defined for stage 4S) occurs.
• Stage 4S: Localized primary tumor as defined by stage 1 or 2 is present but with disseminated disease to liver, less than 10% of bone marrow, skin, or all and is diagnosed in a patient as a newborn to younger than age 1 year.

TNM classification

While a staging system for germ cell tumors originating in nongonadal sites has not been determined, one does exist for germ cell tumors that originate in the gonads. To illustrate this, the TNM classification used to stage primary testicular malignancies is delineated here. This staging system, however, is not used for primary mediastinal germ cell tumors.

Primary tumor (pT)

• pTX - Primary tumor cannot be evaluated.
• pT0 - No evidence of primary tumor (scar noted histologically in testis without evidence of tumor cells)
• pTis - Carcinoma in situ (tumor confined to intratubular areas)
• pT1 - Tumor confined to testis and epididymis with possible invasion of tunica albuginea but not tunica vaginalis; no evidence of vascular or lymphatic invasion
• pT2 - Tumor confined to testis and epididymis with extension through tunica albuginea and involving tunica vaginalis or with evidence of vascular or lymphatic invasion
• pT3 - Tumor invasion of spermatic cord with or without evidence of vascular or lymphatic invasion
• pT4 - Tumor invasion of scrotum with or without vascular or lymphatic invasion

Regional lymph nodes (N)

• NX - Regional lymph nodes cannot be evaluated.
• N0 - No metastasis to regional lymph nodes
• N1 - Metastasis with a lymph node mass of 2 cm or less in greatest dimension or metastases to more than 1 lymph node with none being more than 2 cm in greatest dimension
• N2 - Metastasis with lymph node mass greater than 2 cm but less than 5 cm in greatest dimension or metastasis to more than 1 lymph node with any 1 mass greater than 2 cm but less than 5 cm in greatest dimension
• N3 - Lymph node metastasis with greatest dimension being more than 5 cm

Distant metastasis (M)

• MX - Distant metastasis cannot be assessed.
• M0 - No distant metastasis
• M1 - Distant metastasis
• M1a - Nonregional nodal or pulmonary metastasis
• M1b - Distant metastasis to areas other than nonregional lymph nodes or lung

Serum tumor markers (S)

• SX - Serum markers not available or not performed
• S0 - Serum marker levels within normal limits
• S1 - LDH greater than 1.5 times upper times of normal level and human chorionic gonadotropin (hCG), in mIU/mL, greater than 5000 and AFP (ng/mL) greater than 1000
• S2 - LDH 1.5-10 times upper limits of normal level or hCG (mIU/mL) 5000-50,000 or AFP (ng/mL) 1000-10,000
• S3 - LDH greater than 10 times upper limits of normal level or hCG (mIU/mL) greater than 50,000 or AFP (ng/mL) greater than 10,000

The table below outlines the TNM staging for primary gonadal malignancies.

Table 1. Staging for Primary Gonadal Malignancies Based on TNM Classification (Open Table in a new window)