1. Malignant etiologies (60% to 85% of cases)

a. Lung cancer accounts for 75% of malignancy causing SVC obstruction. Non-small cell lung cancer (NSCLC) accounts for 50% and small cell lung cancer (SCLC) 25% of all cases. SVC syndrome develops in about 3% of patients with lung cancer.

b. Non-Hodgkin lymphoma (NHL) accounts for 10% to 15% of cases of malignant SVC obstruction. Nearly all cases have intermediate-/high-grade histology. Hodgkin lymphoma or low-grade nodular lymphomas rarely cause SVC obstruction.

c. Other malignant etiologies. Other malignant tumors that are less commonly associated with the SVC syndrome include thymoma, primary mediastinal germ cell neoplasms, mesothelioma, and solid tumors with mediastinal lymph node metastases (e.g., breast cancer).

2. Benign etiologies (approximately 30% of cases)

(1) Currently, as many as 50% of cases of SVC syndrome not due to malignancy are attributable to fibrosing mediastinitis, of which the most common cause is an excessive host response to a prior infection with Histoplasma capsulatum. Other infections associated with fibrosing mediastinitis include tuberculosis, actinomycosis, aspergillosis, blastomycosis, and lymphatic filariasis.

(2) Idiopathic fibrosing mediastinitis

(3) Associated with Riedel thyroiditis, retroperitoneal fibrosis, sclerosing cholangitis, and Peyronie disease

(4) After radiation therapy (RT) to the mediastinum

b. Thrombosis of vena cava is usually related to the presence of indwelling intravascular devices. However, considering the frequency of use of central venous access catheters, the incidence of catheter-related SVC thrombosis appears to be low.

(1) Long-term central venous catheterization, transvenous pacemakers, balloon-tipped pulmonary artery catheters, peritoneal venous shunting

(2) Polycythemia vera, paroxysmal nocturnal hemoglobinuria

(3) Behçet syndrome

(4) Idiopathic

(1) Aneurysm of the aorta or right subclavian artery

(2) Dermoid tumors, teratomas, thymoma

(3) Goiter

(4) Sarcoidosis

1. Obstruction and thrombosis. Tumors growing in the mediastinum compress the thin-walled vena cava, leading to its collapse. Venous thrombosis, because of stasis or vascular tumor invasion, often appears to be responsible for acute-onset SVC syndrome.

2. Collateral circulation. The rapidity of onset of symptoms and signs from SVC obstruction depends upon the rate at which complete obstruction of the SVC occurs in relation to the recruitment of venous collaterals. Vena cava obstruction caused by malignancy often progresses too rapidly to develop sufficient collateral circulation, which might alleviate the syndrome. If the obstruction occurs above the azygos vein, the obstructed SVC could then drain into the azygos system. The azygos vein, however, is frequently obstructed by malignancy below its origin.

3. Incompetent internal jugular vein valves, a rare occurrence, cause a dire emergency that is manifested by the filling of these veins. Approximately 10% of patients can experience a rapid demise due to cerebral edema.

C. Diagnosis. The diagnosis of SVC syndrome is usually based on the clinical findings and the presence of a mediastinal mass. CT scan evidence of collateral flow due to a mass is also supportive evidence for the diagnosis. SVC syndrome rarely has to be treated before a histologic diagnosis is made.

1. Symptoms. Patients with malignant disease may develop symptoms of SVC syndrome within weeks to months because rapid tumor growth does not allow adequate time to develop collateral flow. In contrast, fibrosing mediastinitis due to a chronic infection or following RT may not become symptomatic for years.

a. The most common presenting symptoms are shortness of breath (50% of patients), neck and facial swelling (40%), and swelling of trunk and upper extremities (40%). Sensations of choking, fullness in the head, and headache are also frequent symptoms. Chest pain, cough, lacrimation, dysphagia, mental status changes, and convulsions are less frequent.

b. SVC obstruction may occasionally be accompanied by spinal cord compression, usually involving the lower cervical and upper thoracic vertebrae. The SVC syndrome consistently precedes spinal cord compression in these cases. The coexistence of these two complications should be seriously suspected in patients with upper back pain.

2. Physical findings. The most common physical findings are thoracic vein distention (65%), neck vein distention and edema of face (55%), tachypnea (40%), plethora of the face and cyanosis (15%), edema of upper extremities (10%), and paralysis of vocal cords or Horner syndrome (3%). Veins in the antecubital fossae are distended and do not collapse when elevated above the level of the heart. Retinal veins may be dilated on funduscopic examination. Dullness to percussion over the sternum may be present. Laryngeal stridor and coma are grave signs.

a. Chest radiograph demonstrates a mass in >90% of patients. The mass is located in the right superior mediastinum in 75% of cases and is combined with a pulmonary lesion or hilar adenopathy in 50%. Pleural effusions are present in 25% of cases, nearly always on the right side.

b. Chest CT scan. Contrast-enhanced CT can pinpoint the area of obstruction, the degree of occlusion, and the presence of collateral veins. CT scans show absence of contrast in central venous structures with opacification of collateral routes. It can guide fine-needle aspiration.

c. Superior venocavogram. Contrast-enhanced CT with multidetector technology demonstrates the exact site of obstruction and is the procedure of choice in planning stenting procedures. This information is rarely needed for localization of RT ports.

(1) Bilateral upper extremity venography was the gold standard for identification of SVC obstruction and the extent of associated thrombus formation but is infrequently used currently.

(2) MR venography is an alternative approach that may be useful for patients with contrast dye allergy or those for whom venous access cannot be obtained for contrast-enhanced studies.

d. MRI scans of the cervical and upper thoracic vertebrae should be planned in patients with SVC syndrome and back pain, particularly in the presence of Horner syndrome or vertebral destruction on plain films.

4. Histologic diagnosis is important for identifying malignancies that must be treated with cytotoxic agents to improve survival (e.g., NHL, SCLC). After RT is started, tissue diagnosis is difficult to interpret due to necrosis from radiation. Likewise, steroids can affect histology if the underlying diagnosis is lymphoma.

a. Cytology of sputum is positive in 67% of patients and of pleural effusion fluid in nearly all patients with SVC syndrome due to lung cancer.

b. Bronchoscopy and bronchial brushings are positive in 60% of patients. Bronchoscopy and bronchial biopsy in patients with SVC syndrome are rarely associated with serious complications when performed by experienced endoscopists.

c. Lymph node biopsy of palpable nodes can be helpful. Biopsy of palpable scalene nodes in patients with SVC syndrome reveals tumor in 85% of cases; biopsy of nonpalpable scalene nodes reveals tumors in only 30% to 40% of cases.

d. Transthoracic fine-needle aspiration can be attempted for peripheral lesions that cannot easily be approached by bronchoscopy or in whom bronchoscopy results are nondiagnostic. The risk for pneumothorax is small but real.

e. Video-assisted thoracoscopic surgery (VATS) nearly always results in a definitive histologic diagnosis. Bleeding points are usually visualized and controllable.

f. Mediastinoscopy with biopsy risks hemorrhage and other complications. However, when mediastinoscopy is performed on a highly selected group of patients, positive results are obtained in 80% of cases.

g. Bone marrow biopsy is helpful in patients suspected of having SCLC or lymphoma, especially in patients with cytopenia or leukoerythroblastic blood smear. It is especially useful in a young patient with a mediastinal mass.

D. Management. There is little clinical or experimental evidence that unrelieved SVC syndrome is life threatening. Current management guidelines stress the importance of accurate histologic diagnosis prior to starting therapy. Emergency treatment is indicated only in the presence of cerebral dysfunction, decreased cardiac output, or upper airway obstruction. With the exception of RT and/or stent placement for symptomatic SVC syndrome from lung cancer, evidence-based guidelines for management of SVC syndrome are lacking.

1. Endovascular stents. Percutaneous placement of self-expanding metal endoprostheses gives rapid symptomatic relief in 90% to 100% of patients. The stent is placed via a guidewire percutaneously via the internal jugular, subclavian, or femoral vein, under local anesthesia. Many interventionalists
administer heparin as a bolus of 5,000 U during the procedure. One stent may not be sufficient to bridge the entire extent of the stenotic area; sometimes two or even three stents in series are needed. Balloon angioplasty or catheter-directed thrombolysis or mechanical thrombectomy may be necessary in some cases prior to stent placement.

a. Clear indications for placement of endovascular stents for SVC syndrome are patients with

(1) Previously undiagnosed NSCLC, followed by RT

(2) Recurrent symptomatic SVC obstruction previously treated with RT

b. Short-term anticoagulation is often recommended after stent placement, but whether long-term anticoagulation is necessary is uncertain. Reasonable approaches include warfarin (1 mg daily with the goal of maintaining an INR of <1.6) or dual antiplatelet therapy (e.g., clopidogrel 75 mg daily plus aspirin) for 3 months after stent placement.

2. RT is indicated alone in patients with symptomatic SVC syndrome caused by NSCLC (possibly following placement of an endovascular stent) and in combination with chemotherapy for SCLC and certain types of lymphoma. The total dose of RT varies between 3,000 and 5,000 cGy, depending on the general condition of the patient, severity of the symptoms, anatomic site, and histologic type of underlying malignant tumor. Symptoms may resolve dramatically even without establishment of patency of the SVC.

a. Response. RT is associated with complete relief of symptoms of SVC obstruction within 2 weeks in about 70% of patients with lung cancer. Relief of symptoms, however, may not be achieved for up to 4 weeks, and approximately 20% of patients achieve no relief from RT. Furthermore, the benefits of RT are often temporary, with many patients developing recurrent symptoms before dying of the underlying disease.

b. Median survival is about 10 months for SCLC and 3 to 5 months for NSCLC.

3. Chemotherapy is indicated as initial treatment in patients with NHL, SCLC, germ cell cancer, and (possibly) breast cancer with symptomatic SVC syndrome. In these settings, the clinical response to chemotherapy alone is usually rapid. Furthermore, these patients can often achieve long-term remission and durable palliation with standard treatment regimens. In certain situations (e.g., limited stage SCLC, some subtypes of NHL), the addition of RT to systemic chemotherapy may decrease local recurrence rates and improve overall survival.

4. Emergency treatment. For patients with clinical SVC syndrome who present with stridor, respiratory compromise, or depressed central nervous system function, emergent treatment with endovascular stenting followed by RT is recommended.

5. Supportive therapy. Airway obstruction should be corrected and hypoxia treated by oxygen administration. The head should be raised to decrease hydrostatic pressure and head and neck edema. Corticosteroids reduce brain edema and improve the obstruction by decreasing the inflammatory reaction associated with the tumor and RT. Diuretics may be helpful.

6. Anticoagulants and antifibrinolytic agents may be helpful if the underlying cause of the SVC thrombosis is an indwelling catheter. Removal of the catheter is indicated, in conjunction with systemic anticoagulation. These agents rarely result in disappearance of caval thrombosis but may be used in conjunction with stent placement. When extensive thrombosis occurs as a complication of SVC stenosis, local catheter-directed thrombolytic therapy may be of value to reduce the length of the obstruction and the number
and length of stents required, and also reduce the risk of embolization. The thrombus may also be removed by mechanical thrombectomy, although this is used less often than thrombolysis.

7. Surgical decompression of acute SVC obstruction and incompetence of jugulosubclavian valves consists of reconstructing or bypassing the SVC using a spiral saphenous vein graft or left saphenoaxillary vein bypass, which can be done under local anesthesia. The experience with this procedure has been mainly in SVC associated with nonmalignant causes.

1. Occurrence. The lungs are the most frequent site of distant metastases for nearly all malignant tumors except those arising in the gastrointestinal tract.

2. Dissemination to the lungs. Malignant melanoma, bone and soft tissue sarcomas, trophoblastic tumors, and renal cell, colonic, and thyroid carcinomas tend to spread to vascular routes and usually produce discrete metastatic lung nodules. Malignant tumors of the breast, pancreas, stomach, and liver may spread directly through lymphatic channels, involve mediastinal lymph nodes, and produce diffuse interstitial or lymphangitic infiltration, focal or segmental atelectasis, and pleural metastasis or effusion. Germ cell tumors and sarcomas may also involve the mediastinum.

a. Endobronchial metastasis is not uncommon in Hodgkin lymphoma, hypernephroma, and breast carcinoma.

b. Solitary pulmonary metastasis is relatively uncommon but can occur in patients with malignant melanoma or carcinoma of the breast, uterus, testis, kidney, or urinary bladder.

c. Isolated pulmonary metastasis. Osteogenic sarcoma, soft tissue sarcoma, and testicular carcinoma are the tumors that are most likely to have lung metastases without involvement of other organs. Renal and uterine carcinomas may also produce isolated lung metastases. Malignant melanoma rarely has pulmonary metastases without other organ involvement as well.

d. Lymphangitic pulmonary metastases are rapidly lethal. Median survival is <2 to 3 months for patients without effective treatment.

e. Central pulmonary metastases. Malignant tumors that invade hilar or mediastinal structures may result in SVC obstruction, major airway obstruction, postobstructive pneumonia, and invasion of the pericardium, myocardium, or esophagus.

B. Diagnosis. A new pulmonary lesion in a patient with a known malignancy may represent a metastasis, a second primary lung cancer (particularly if the patient is a smoker), or a benign lesion.

1. Symptoms and signs. Most patients with solitary or multiple pulmonary metastases do not have symptoms; the presence of symptoms portends a poor prognosis. The patients who are most likely to be symptomatic with cough, chest pain, hemoptysis, or progressive dyspnea have central, hilar, mediastinal, or lymphangitic metastatic involvement. Dyspnea out of proportion to the radiographic findings in the absence of radiologic findings should raise suspicion of lymphangitic spread. Paraneoplastic syndromes such as hypertrophic pulmonary osteoarthropathy can occur with sarcoma or lung cancer. Physical examination may also be absolutely normal.

2. Radiographic studies. No current imaging modality can distinguish a benign tumor from a malignant tumor or a primary tumor from a metastasis. Plain films do not detect lesions smaller than 1 cm in diameter. High-resolution
helical CT detects approximately 25% more nodules than conventional CT and nodules as small as 2 to 3 mm; however, this improved sensitivity is at the expense of specificity.

a. Metastatic nodules are typically well-circumscribed, round deposits with smooth margins and are predominantly subpleural or located in the outer third of the lung fields. In contrast, primary lung cancers are usually single, often have irregular borders and associated linear densities, and are more often located centrally.

b. When multiple nodules are present, the probability of metastatic disease increases significantly. However, multifocal abnormalities may be seen with primary bronchioloalveolar carcinomas, which may present with multiple pulmonary nodules and ground glass opacification, and with severe acute and chronic nonmalignant pulmonary disease.

c. About half of patients with lymphangitic lung metastases have normal chest radiographs; the remainder of patients have nonspecific interstitial changes.

3. Positron emission tomography (PET). The results of the PET scans cannot be used reliably to classify CT-discovered thoracic lesions as benign or malignant. The main value of PET is for detecting extrathoracic disease.

4. Sputum cytology is positive in only 5% to 20% of patients with nodular metastases.

5. Pulmonary function studies with lymphangitic metastases characteristically produce a restrictive defect with hypocapnia but without hypoxemia. Restrictive lung disease can be confirmed by finding impaired diffusion capacity of the lung for carbon monoxide DLCO and low residual and total lung volumes.

6. Bronchoscopy (with or without endobronchial ultrasound) is indicated as part of the evaluation in cases of centrally located lesions identified on CT, in patients with symptoms of airway involvement, and for cell types that are prone to endobronchial involvement, such as breast, colon, and renal cell cancer.

C. Resection (metastasectomy) of pulmonary metastases. Aggressive surgical resection of lung metastases in appropriately selected patients offers a chance for extended disease-free survival that would not be possible with systemic therapy. Retrospective experience with selected patients has shown that the overall actuarial 5- and 10-year survival rates after complete metastasectomy are about 35% and 25%, respectively.

a. Head and neck cancers. Patients with a history of head and neck carcinoma (especially laryngeal carcinoma) and who develop a lung nodule should be approached as if they have developed a new primary lung cancer. There is no way to differentiate a solitary metastasis from a second primary cancer in these patients.

b. Testicular carcinoma. Solitary lung nodules in the treated patient may develop into malignant teratomas or be lesions harboring active cancer. These have to be considered for resection.

c. Sarcomas. Patients with sarcomas are routinely followed with CT scans of the chest, monitoring for the development of pulmonary metastases amenable to resection, because the lungs are frequently the only site of metastasis. Osteogenic sarcomas are best treated with preoperative chemotherapy if the tumors are multiple.

d. Breast cancer. Resection of pulmonary metastases that are solitary in patients with a previous history of breast cancer is appropriate as 50% of these patients may have a benign lesion or a new primary lung cancer.

a. Completeness of resection. Nearly all reports indicate that complete resection of metastatic disease is associated with the best outcomes.

b. Disease-free interval (DFI). Higher 5-year survival rates are observed for patients with a DFI of >36 months compared to patients with a DFI of <1 year.

c. Number of metastases. A single or few and unilateral metastases have a better prognosis than many or bilateral metastases.

d. Delaying intervention after a pulmonary metastasis is first identified may allow initially occult metastases to become clinically apparent; if in the lungs, a more complete resection would be permitted; if at other sites, unhelpful surgery would be avoided. On multivariate analysis, waiting more than 3 months from the detection of pulmonary metastases to resection was an independently significant prognostic factor for survival.

a. Thin-section, high-resolution helical CT is preferred over conventional CT in order to maximize detection of all sites of intrathoracic disease.

b. PET scan is indicated to identify any extrathoracic foci of disease. Even if there is no FDG uptake in the pulmonary nodules, they should be resected for both diagnostic and therapeutic purposes.

c. Brain imaging for patients who have tumors that frequently metastasize to the brain (e.g., breast cancer, melanoma)

d. Evaluation of the mediastinal lymph nodes as would be done for a patient with a primary lung cancer. Surgical staging of the mediastinal and hilar lymph nodes prior to pulmonary metastasectomy appears to provide diagnostic and prognostic information.

e. Preoperative CT-guided fine-needle aspiration biopsy is a useful means to obtain tissue if the diagnosis of metastatic disease is in question, if the patient is a poor or borderline operative candidate, or if the patient has a primary tumor (e.g., testicular germ cell tumor, lymphoma) for which surgery may not be necessary.

4. Criteria for resection. Video-assisted thoracoscopic surgery (VATS) can be used for patients with one or a limited number of small metastases in the periphery of one lung. The type of histology, number of lesions, and whether they are bilateral do not appear to contraindicate resection or adversely influence the survival if the selection criteria discussed below are adhered to. Prognosis is best for patients with a long DFI (>36 months) and a solitary metastasis. Wedge resection is the recommended treatment of pulmonary metastases in patients who meet all of the following criteria:

a. The patient’s general medical condition and pulmonary function status are suitable for surgery.

b. The primary tumor is under control (no evidence of local recurrence) or controllable.

c. Metastases are limited to the lung (no uncontrollable extrapulmonary tumor exists), and all metastases appear to be completely resectable.

d. Resection of one or more lung lesions may also be indicated in a patient with a known malignancy when a new primary lung cancer cannot be excluded.

e. No better method of treatment exists.

5. Timing for metastasectomy depends upon the anticipated surgical approach (open thoracotomy vs. VATS). VATS metastasectomy may be selected for an isolated peripheral nodule in a favorable location because recovery time and
surgical risk are minimal. However, open thoracotomy would be required for a deep nodule or numerous nodules of varying sizes. Delaying open surgery and performing repeat CT scanning for 2 to 3 months allow the full extent of disease to be revealed and prevent unnecessary surgery without affecting prognosis.

6. Uncertain issues regarding pulmonary metastasectomy. There are no established guidelines as to appropriate patient selection and no consensus regarding a preference for open thoracotomy versus a VATS procedure. Whether the presence of documented mediastinal nodal involvement should influence the decision to resect the parenchymal metastases is controversial.

1. Local control. RT is useful for palliation of local complications of metastatic tumors, such as bronchial obstruction, vena cava obstruction, hemoptysis, or pain caused by tumor invasion of the chest wall. Stereotactic RT, radiofrequency ablation, or cryotherapy may offer alternative options.

2. Chemotherapy or hormonal therapy can be applied in responsive tumors. Germ cell and trophoblastic tumors can be cured despite the presence of pulmonary metastasis.

3. Lymphangitic lung metastases represent an emergent problem in diagnosis and management. Symptomatic relief of dyspnea can often be rapidly achieved with prednisone, 60 mg PO daily. Chemotherapy is effective in responsive tumors. Hormonal manipulation is usually ineffective or achieves a response too slowly to be helpful. Symptoms from refractory lymphangitic lung metastases may be palliated by low-dose lung irradiation.

4. Terminal problems in patients with lung cancer such as hemoptysis and air hunger are discussed in Chapter 5, Section VI.C.

1. Etiology. Malignant tumors causing pleural effusions are as follows (in order of decreasing frequency): lung cancer (especially adenocarcinoma), breast carcinoma, lymphoma, unknown primary, gastric carcinoma, ovarian carcinoma, melanoma, and sarcoma.

2. Types of malignant effusions. Pleural effusions are usually caused by direct involvement of the pleura by tumor or by lymphatic or venous obstruction or both. Central effusions, particularly those caused by lymphoma or nerve tissue tumors, may be chylous and have high-triglyceride and low-cholesterol concentrations. Atelectasis, pneumonia, and severe hypoalbuminemia that complicate malignancy may also cause pleural effusion.

B. Natural history. Malignant pleural effusion is a sign of advanced disease. The pleural space is progressively obliterated by fibrosis and serosal tumor. Patients with carcinomatous pleural effusions have a mean survival of 3 months from the time of diagnosis, but this varies with the responsiveness of the underlying tumor to systemic therapy.

C. Differential diagnosis. The differentiation of pleural fluid from pleural fibrosis or pulmonary consolidation may not be possible by physical examination or chest radiographs. Aspiration of fluid may be difficult because of loculation. Ultrasonography is helpful for identifying and sampling small pockets of effusion.

1. Symptoms and signs. Cough and dyspnea are the most common symptoms of pleural effusion. Dullness to percussion, decreased breath and voice sounds, decreased vocal fremitus, and egophony are the classic physical findings. The trachea may be shifted to the side opposite the effusion. Thickened pleura
from fibrosis or neoplastic involvement also produces dullness and decreased vibration.

2. Thoracentesis should be performed in any patient with a suspected malignant, infectious, or empyemic pleural effusion. Pleural fluid should be assayed for protein, lactate dehydrogenase (LDH) level, pH, glucose, cell count, and cytology and stained and cultured for bacteria (especially mycobacteria) and fungi. If the effusion appears chylous, triglyceride and cholesterol concentrations should be measured. Malignant effusions are usually exudative but may be transudative. Results of fluid examination frequently are nonspecific.

a. Discrimination between transudates and exudates is facilitated by relating the concentration of key parameters in the pleural fluid to those values in the serum or to the laboratory’s upper limit of normal (ULN). Diagnostic rules vary among systems of classification. Characteristics for exudates in various systems are

– Pleural fluid/serum ratio for protein >0.5

– Pleural fluid protein >2.9 g/dL (29 g/L)

– Pleural fluid/serum LDH ratio >0.6

– Pleural fluid LDH >0.45× or >0.67× ULN for serum LDH

– Pleural fluid cholesterol >45 mg/dL (1.165 mmol/L)

b. Cytology is positive in half of malignant pleural effusions. Repeated cytologic analysis increases the yield if the first thoracentesis is negative.