Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration

For evaluation of mediastinal adenopathy or other lesions in the middle mediastinum, transbronchial needle aspiration (TBNA) via the fiberoptic bronchoscope offers a less invasive option to surgical mediastinoscopy. Although few significant complications have been reported, the sensitivity of blind TBNA is low, ranging from 14% to 50%.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a recent technology that has significantly improved the ability of pulmonologists to diagnose and stage non–small cell lung cancer in a minimally invasive manner. With the advent of a curvilinear ultrasound probe integrated at the end of the bronchoscope, TBNA with a 22-gauge needle can be performed under real-time ultrasonographic guidance. The ability to visualize the area of interest as well as adjacent vascular structures has vastly improved diagnostic yields. Upper and lower paratracheal, subcarinal, and hilar lymph nodes are readily accessible by EBUS-TBNA, as is any mediastinal or hilar lesion that is adjacent to the large airways. EBUS-TBNA has the advantage over mediastinoscopy in accessing the posterior subcarinal lymph nodes as well as hilar nodes or masses, in addition to being an ambulatory procedure with lower associated health care costs.

While the efficacy of EBUS-TBNA is now firmly established in the evaluation of lung cancer, there is also an increasing role for the initial evaluation of isolated mediastinal adenopathy due to other conditions such as sarcoidosis. In a randomized controlled trial of 50 patients with clinically suspected sarcoidosis due to the presence of mediastinal and hilar adenopathy, the diagnostic yield of EBUS-TBNA was superior to blind TBNA, with a sensitivity of 83% and specificity of 100%. In a prospective trial of 77 patients with isolated mediastinal adenopathy, a specific diagnosis of sarcoidosis, tuberculosis, lymphoma, or other malignancy was made in 67 of them, thus obviating the need for a more invasive surgical mediastinoscopy. EBUS-TBNA can be useful in providing a definitive diagnosis of primary or recurrent lymphoma; however, its role in the initial diagnosis of mediastinal lymphoproliferative disorders is controversial because the amount of tissue provided may not be adequate for histologic subtyping.

Endoscopic Ultrasound-Guided Needle Aspiration and Biopsy

Endoscopic ultrasound (EUS)–guided sampling relies on the placement of biopsy needles that are passed through the working channel of a gastroscope. The proximity of the esophagus to mediastinal sites relatively inaccessible to mediastinoscopy, such as the posterior subcarinal lymph nodes, makes this approach particularly useful in selected cases. EUS-guided biopsy has similar sensitivity as PET for determining inoperability in lung cancer and, importantly, superior specificity (100% vs. 72%). In selected cases, it can confirm the presence of mediastinal metastases and thereby obviate the need for surgical staging procedures.

Percutaneous Needle Aspiration and Biopsy

Percutaneous needle aspiration and biopsy of mediastinal masses, usually in the anterior compartment, can be performed using ultrasound or, more often, CT guidance ( Fig. 83-7 ). Percutaneous needle aspiration of the mediastinum has acceptable morbidity and yields comparable to those from percutaneous biopsy of pulmonary lesions. As with TBNA, serious bleeding is seldom encountered, and accurate diagnosis of a wide variety of lesions has been reported.

CT-guided needle aspiration of an anterior mediastinal mass.

The image shows the needle entering the mass by passing lateral to the sternum and medial to the internal mammary vessels ( arrow, left internal mammary artery). Associated findings include a pretracheal lymph node and bilateral pleural effusions.

Mediastinoscopy

Mediastinoscopy allows direct inspection and biopsy of lymph nodes or other masses in the superior portion of the anterior mediastinum. Cervical mediastinoscopy provides access to the paratracheal and subcarinal lymph nodes, whereas an anterior mediastinotomy (otherwise known as an anterior or parasternal mediastinoscopy) provides access to the lymph nodes in the aortopulmonary window. Although more invasive than a percutaneous or endobronchial approach, mediastinoscopy has the advantage of providing the entire lymph node for histologic examination, rather than the cellular aspirates or small tissue fragments produced by needle biopsy techniques. Mediastinoscopy is most frequently used in the staging of bronchogenic carcinoma, but has utility in evaluating mediastinal adenopathy or mass lesions of other etiologies. Either frozen section or imprint cytology methods can provide rapid, accurate results and facilitate immediate decisions about the feasibility of curative resection.

Mediastinal anatomy from the perspective of the surgeon performing a mediastinoscopy is different from that based on the lateral chest radiograph as described earlier. For mediastinoscopy, structures are considered according to whether they lie anterior, posterior, or immediately to the right or left of the trachea. Mediastinoscopy is performed using general anesthesia, but is typically an outpatient procedure when subsequent thoracotomy is not planned to follow immediately.

Mediastinoscopy is safe and well tolerated. Complications of mediastinoscopy include pneumothorax, hemorrhage, recurrent laryngeal nerve or phrenic nerve paralysis, injury to the trachea, esophageal perforation, thoracic duct laceration, air embolism, and mediastinitis.

Video-Assisted Thoracoscopic Surgery

Biopsies of mediastinal lymph nodes can also be performed by video-assisted thoracoscopic surgery (VATS). VATS provides access to the hilar nodes and inferior pulmonary ligament lymph nodes on both sides. Additionally, on the right side, VATS can provide access to the right paratracheal lymph nodes and subcarinal nodes. Left-sided VATS can provide access to the aortopulmonary nodes. VATS can also be a tool for the evaluation of pleural and lung abnormalities in the management of mediastinal diseases. After dissection through the mediastinal pleura, mediastinal lymph nodes can be sampled to aid in the staging of malignancies such as esophageal carcinoma and for the diagnosis and resection of primary mediastinal tumors and cysts. VATS requires a general anesthetic, chest tube placement at the conclusion of the procedure, and typically a limited stay in the hospital.

Thymic Neoplasms

Thymoma is the most common neoplasm arising in the anterior mediastinum and is increasingly recognized in the course of thorough evaluations of patients with myasthenia gravis. It remains a rare tumor, with an overall incidence of 0.13 per 100,000 person-years in the United States. The peak incidence of thymomas is between the ages of 40 and 60 years and is higher in Asians and African Americans, with equal gender predilection.

Although most thymomas are not biologically aggressive, about one third of thymomas found have already invaded their capsules. Advanced disease involves extension into local structures and transdiaphragmatic extension into the abdomen and pericardial involvement, but lymphogenous and hematogenous metastases are rare. The histologic classification remains a subject of debate and revision. The current World Health Organization classification system, which is based on histologic features, does not accurately predict clinical outcome, thus treatment of patients has been based historically on the presence and degree of tumor invasion into microscopic and local structures. Most clinicians use the Masaoka clinical staging system, which is based on the degree of invasion of the tumor through the capsule into adjacent structures. Moran and colleagues recently proposed a new staging system in which the overall prognosis and recurrence is based on extent of tumor infiltration. Currently the International Thymic Malignancies Interest Group (ITMIG) and the International Association for the Study of Lung Cancer (IASLC) are collaborating on developing a new TNM-based classification system, which is expected in 2017.

Clinically, the majority of patients with thymoma are asymptomatic, while one-third of patients will present with nonspecific chest pain, cough, or dyspnea due to local tumor effects. Forty to 70% have at least laboratory evidence of one or more of the two dozen systemic “parathymic” syndromes that have been recognized. Thymomas are associated with numerous systemic syndromes, most of which appear to be autoimmune in origin. The most familiar of these is myasthenia gravis, reported in 10% to 50% of patients with thymoma and thought to be due to autoantibodies to the postsynaptic acetylcholine receptor. Other associated syndromes include pure red blood cell aplasia, myocarditis, and hypogammaglobulinemia. Patients with thymoma also have an increased incidence of collagen vascular disease, Whipple disease, and malignancy elsewhere in the body.

On chest radiography, thymomas appear as an ovoid, smooth or lobulated unilateral mass near the junction of the heart and great vessels ( Fig. 83-9 ). Compared with thymic hyperplasia, which is typically symmetrical, thymoma usually distorts the gland’s normal shape and extends to one side. On CT scan, most thymomas present as a solid 5- to 10-cm anterior mediastinal mass outlined by fat; up to one third of thymomas contain cystic, necrotic, or hemorrhagic areas that enhance heterogeneously. Contrast CT is necessary for the staging of thymoma, specifically for discerning vascular involvement. MRI can help distinguish benign cysts from a cystic thymoma or thymic carcinoma. At this time, nuclear medicine has little role in the evaluation of thymoma. Due to their relatively indolent nature, most thymomas have low FDG uptake, which limits the utility of PET imaging to discern a benign from a malignant thymic mass.

Thymoma.

A, Frontal chest radiograph shows a smoothly marginated mass along the right side of the mediastinum ( arrows ). B, Axial magnetic resonance T1-weighted image through the base of the heart shows that the mass ( arrows ) is slightly hyperintense compared to the skeletal muscle and resides within the anterior mediastinum. Note the smooth, well-defined margins of the mass, consistent with an encapsulated thymoma.

(Courtesy Michael Gotway, MD.)

The mainstay of therapy for thymomas is surgical resection, which provides the best chance for an optimal prognosis. Adjunctive treatment with postoperative radiotherapy is typically provided, and the addition of preoperative or adjuvant chemotherapy appears promising for more advanced stages.

Patients whose tumors are fully encapsulated with no evidence of invasion can expect postoperative survival equal to that of the general population. Invasive tumors have a poorer prognosis, with 50% to 77% 5-year and 30% to 55% 10-year survival. Thymoma recurs after resection in nearly a third of patients. The largest and most recent retrospective survey of thymic tumors from the European Society of Thoracic Surgeons database showed that higher Masaoka stage (with evidence of invasion), incomplete resection, and nonthymoma histology were factors in recurrence and worsening survival.

Thymic carcinoma is an aggressive epithelial malignancy that invades locally and frequently metastasizes. This rare cancer develops predominantly in middle-aged men, who present with symptoms of cough, dyspnea, and chest pain as well as nonspecific systemic symptoms. On imaging, thymic carcinomas are heterogenous masses with areas of necrosis and calcifications. They are highly FDG-avid on PET scan. The prognosis, which depends on the histologic grade and the anatomic stage, is generally poor. Surgical resection is the treatment of choice; chemotherapy and radiation therapy are advocated for unresectable disease.

Carcinoid tumors occasionally arise in the thymus. They may cause Cushing syndrome and be associated with multiple endocrine adenomatosis. Locally invasive carcinoids may be difficult to resect completely, but characteristically have a prolonged clinical course. Interestingly, the thymus is also a common site for mediastinal Hodgkin lymphoma, and normal thymic tissue may enlarge following chemotherapy for lymphoma (a process termed thymic rebound ) ( eFig. 83-25 ), mimicking recurrence of the primary disease. Other thymic mass lesions include benign conditions such as thymic hyperplasia ( eFig. 83-26 ), thymic cysts, and lipothymomas (seeVideo 83-5 and eFig. 83-11 ).

Germ Cell Tumors

Approximately 10% to 12% of primary mediastinal masses are derived from multipotent germ cells that migrated abnormally during early embryonic development. These neoplasms are classified into three groups: benign teratoma, seminoma, and nonseminomatous germ cell tumors.

Teratomas, the most common germ cell tumors, are by definition made up of tissues foreign to the area in which they arise. Ectodermal derivatives predominate, but structures originating in all three primary germ cell layers may be found. Dermoid cyst refers to a lesion that contains only the epidermis and its derivatives. Teratomas arise most often in young adults, but have been reported in all age groups; men and women are affected with equal frequency. Most patients with teratomas have symptoms caused by the tumor; only about a third are asymptomatic. Usual symptoms are pain, cough, and dyspnea. Teratomas can rupture into the pleural space or into the pericardium. If the tumor erodes into a bronchus, the patient may have hemoptysis or even expectorate differentiated tissue such as hair (trichoptysis) or sebaceous material.

On chest radiographs, teratomas appear smooth, rounded, and circumscribed if they are cystic. Solid lesions can appear lobulated and asymmetric. On CT scans (seeVideo 83-4 and eFig. 83-10 ), soft tissue, fat, and calcification (occasionally, fully formed teeth and bone) can be identified, rendering this one of few mediastinal tumors that can be diagnosed confidently before operation ( Fig. 83-10 ). All teratomas should be resected due to malignant potential and effects of impingement on adjacent vital structures. In malignant teratoma, adjuvant combination chemotherapy may result in improved survival.

Teratoma.

Axial CT image through the base of the heart shows a large right-sided anterior mediastinal mass with heterogenous attenuation. Elements of calcium, soft tissue, and fat (*) are present. The presence of fat within an anterior mediastinal mass is most consistent with teratoma.

(Courtesy Michael Gotway, MD.)

Seminomas and nonseminomatous germ cell tumors are malignant and nearly always cause symptoms. These lesions appear as a large anterior mediastinal mass on chest imaging (Video 83-9 and eFig. 83-29 ). Seminomas are seen almost exclusively in men, usually in the third decade of life. Most patients seek medical attention because of chest pain, dyspnea, cough, hoarseness, or dysphagia. Seminomas are aggressive malignant tumors that extend locally and metastasize distantly, usually to skeletal structures. The tumor can obstruct the SVC. They may secrete human chorionic gonadotropin, but not alpha-fetoprotein. Factors associated with a poor prognosis include age older than 35 years, SVC obstruction, supraclavicular, cervical, or hilar adenopathy, and fever. Seminomas are extremely radiosensitive and may respond dramatically to chemotherapy, even in cases with dissemination. With aggressive cisplatin-based regimens, long-term survival for all mediastinal seminomas is approximately 80%.

Nonseminomatous mediastinal germ cell tumors include embryonal cell carcinoma and choriocarcinoma. Like seminoma, these tumors develop mainly in men in the third and fourth decades and are usually symptomatic. These malignancies carry a poorer prognosis relative to cancers arising from the gonads. Embryonal cell carcinoma is also called endodermal sinus or yolk sac tumor (Video 83-10 and eFig. 83-30 ). These highly aggressive tumors often secrete human chorionic gonadotropin, alpha-fetoprotein, or carcinoembryonic antigen. Human chorionic gonadotropin may also produce clinical manifestations, such as gynecomastia, in 50% of patients. Associations have been noted with Klinefelter syndrome and with hematologic malignancy. Most patients present with disseminated disease, and the prognosis has been less favorable than in seminoma. Cisplatin-based treatment regimens have markedly improved the outcome, with more than 50% of patients achieving long-term survival. Long-term survival may also be possible in those who undergo a complete surgical resection following chemotherapy. Even disseminated and refractory malignant germ cell tumors may respond to aggressive chemotherapy and salvage regimens involving bone marrow transplantation.

Lymphoma

Lymphoma is an important cause of mediastinal mass, and is distinguished from other mediastinal lesions in that management is primarily medical, not surgical. In most series, lymphoma represents between 10% and 20% of mediastinal masses in both adults and children. Lymphomas are the most common anterior and middle mediastinal masses in children; a majority of pediatric patients with Hodgkin lymphoma (HL) and half of those with non-Hodgkin lymphoma (NHL) present with a mediastinal mass. HL has a bimodal distribution, arising in adolescents and young adults as well as in those older than 50, whereas NHL arises most commonly in older adults.

Primary mediastinal B-cell lymphoma (PMBL) is a distinct subset of NHL that has a similar clinical presentation as classic HL of the nodular sclerosing subtype. Both present in the third or fourth decade of life and tend to affect females. These tumors present as a bulky anterior mediastinal mass involving the thymus (see Fig. 83-6 ). SVC syndrome is a common presentation of PMBL, less so for HL (seeVideo 83-2 and eFig. 83-2 ), which can involve the hilar nodes and lung parenchyma. However, there are distinct and nonoverlapping histologic features. HL is characterized by the Hodgkin/Reed Sternberg cell in a nodular growth pattern with a specific immunophenotype of CD30+, CD45−, and CD15+ in 85% of cases. PMBL is histologically characterized by an infiltrate of large cells in a diffuse pattern with an immunophenotype of a mature B lymphocyte expressing CD20. A B-cell lymphoma that exhibits histologic features of both PMBL and HL has been named “gray zone lymphoma.”

Distinguishing HL from PMBL is important for guiding therapy, thus tissue biopsy is indicated. The current standard of treatment for early stage, bulky mediastinal disease is combined modality therapy, consisting of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and radiation. Optimal therapy for nonbulky mediastinal HL is controversial; recent clinical trials suggest no difference in overall survival but an increase in risk for disease progression with chemotherapy alone. The benefits of radiation therapy must be balanced with the risk for serious late complications, including pulmonary fibrosis, cardiovascular disease, and secondary malignancies such as breast and lung cancer.

PMBL is treated with immunochemotherapy, which includes rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimens, followed by radiation. Whereas these standard dose regimens have a cure rate of up to 75%, more recent evidence has shown that dose intensity may improve outcomes in PMBL. DA-EPOCH (dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone, rituximab) has been shown to confer an overall survival of 97% without the need for radiation treatment in the majority of patients. The prognosis of HL and NHL has improved strikingly in the past 2 decades as staging of the disease has been refined and as more effective and less toxic combinations of radiotherapy and chemotherapy have evolved. With new chemotherapy regimens, radiotherapy may not be a necessary part of the treatment plan for PMBL. PET scan, which is often used to restage aggressive lymphomas, appears to have a high negative predictive value and may be helpful for clinicians in deciding when to omit radiotherapy after primary chemotherapy; this is being investigated in an ongoing clinical trial. Effective salvage regimens including bone marrow transplantation have been developed to treat relapsed disease. HL is curable in approximately 75% of patients, although late toxicities of treatment contribute significantly to mortality.

Thyroid Lesions

In surgical series, ectopic thyroid glands account for fewer than 10% of mediastinal masses but, in clinical practice, these are probably more common. Thyroid tissue within the mediastinum is of two distinct origins. Most commonly, a cervical goiter extends substernally into the anterior mediastinum. Primary intrathoracic goiter, presumably originating from an embryonic nest of heterotopic thyroid tissue, is rare. Most such goiters are in the anterior mediastinum, but they may arise in the middle or posterior mediastinum as well. Intrathoracic goiter presents predominantly in middle aged or older women. Although it is usually asymptomatic, goiter may cause hoarseness, cough, or swelling of the face and arms. Intrathoracic thyroid tissue is easily recognized by radioactive iodine scanning, as long as the scan is completed before intravenous iodinated contrast injection, which may block iodine uptake for weeks. It may be suspected on the basis of high radiodensity on CT scans, particularly after iodinated contrast injection. Treatment is surgical resection.

Parathyroid Lesions

Mediastinal parathyroid tissue accounts for up to 10% of cases of hyperparathyroidism, and the mediastinum is the most common site for ectopic parathyroid adenomas in surgically resistant hyperparathyroidism. Half of ectopic parathyroid adenomas lie in the anterior mediastinum, usually near the thymus. Parathyroid cysts may enlarge sufficiently to appear as a mass on the chest radiograph and to produce symptoms, but ectopic tissue may be difficult to locate. Evaluation of the lesion is typically conducted using CT angiography, ultrasound, MRI, and the sensitive technetium-99m sestamibi scanning. Selective arteriography and venous sampling for parathormone levels have largely been supplanted by sestamibi radionuclide scanning. Parathyroid adenomas are cured by complete resection, and resection via VATS is increasingly advocated. Parathyroid carcinoma may be functional, resulting in varying degrees of hyperparathyroidism, but is also locally invasive and may metastasize. Cure is possible with aggressive surgical management that may be guided by imaging and functional localization studies.

Mesenchymal Tumors

Included in this group of unusual mediastinal masses are lipomas, fibromas, mesotheliomas, and lymphangiomas (see Table 83-4 ). They arise from connective tissue, fat, smooth muscle, striated muscle, blood vessels, or lymphatic channels and can be found in any region of the mediastinum. Histologically and clinically, they are not substantially different from their counterparts elsewhere in the body. Unless the lesion is very large, the presence of symptoms usually indicates that the lesion is malignant.

Lipoma is the most common mesenchymal tumor of the mediastinum and is most often located in the anterior mediastinum. It may be encapsulated or unencapsulated, appearing as a smooth and rounded lesion with well-defined margins. The characteristic low density of lipomas on CT images ( Fig. 83-11 ) permits a confident diagnosis unless there is associated heterogeneity, invasion of surrounding tissues, or poor demarcation of the mass’s perimeter, in which case malignancy (liposarcoma or lipoblastoma) or teratoma must be excluded. Considerably more common than lipoma is mediastinal lipomatosis, or generalized overabundance of histologically normal unencapsulated fat (see Fig. 83-2 ). Mediastinal lipomatosis appears on the conventional radiograph as a smooth widening or bulging of normal mediastinal contours, and its low homogeneous CT density confirms the diagnosis. Mediastinal lipomatosis does not compress or displace other mediastinal structures.

Lipoma.

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