Lung, Metastases

 

Background: Pulmonary metastases are common. They most frequently occur with tumors that have rich systemic venous drainage. Examples include renal cancers, bone sarcomas, choriocarcinomas, melanomas, testicular teratomas, and thyroid carcinomas. Most pulmonary metastases arise from common tumors such as breast, colorectal, prostate, bronchial, head and neck, and renal cancers. The detection of pulmonary metastases is crucial in the treatment of patients with cancer.

 

Pathophysiology: Pulmonary nodules are the most common manifestation of secondary neoplastic disease in the lungs. They are usually derived from tumor emboli arising from invasion of tumor capillaries. The tumor emboli drain via the systemic veins and pulmonary arteries. They subsequently lodge in the small pulmonary arteries or arterioles and extend into adjacent lung tissue. Pulmonary nodules are usually multiple, spherical, and variably sized. Metastases that occur via bronchial arteries, pulmonary lymphatics, transbronchial aspiration, and across the pleural cavity are less common.

Lymphangitis carcinomatosis is usually the result of hematogenous metastases to small pulmonary capillaries, with secondary invasion of peripheral pulmonary lymphatics. Retrograde extension from hilar or mediastinal nodes or direct invasion from diaphragmatic lymphatics is less common. Breast, lung, stomach, pancreas, and prostate cancers are the most common tumors that result in lymphangitis. Endobronchial metastases are rare, and they are associated with tumors of the breast, colon, and kidney, as well as sarcoma and melanoma.

 

Frequency:

  • In the US: Autopsy series have demonstrated that pulmonary metastases are present in 20-54% of all patients who die of cancer. The incidence of pulmonary metastases during the course of the disease or at presentation is obviously less than that of the autopsy series. The incidence of lung metastases varies with the primary neoplasm (see the Table).

    Incidence of Pulmonary Metastases According to Site

     
    Primary Tumor Frequency at Presentation, % Frequency at Autopsy, %

     

    Choriocarcinoma 60 70-100

     

    Melanoma 5 66-80
    Testis, germ cell 12 70-80
    Osteosarcoma 15 75
    Thyroid 7 65
    Kidney 20 50-75
    Head and neck 5 15-40
    Breast 4 60
    Bronchus 30 40
    Colorectal <5 25-40
    Prostate 5 15-50
    Bladder 7 25-30
    Uterus <1 30-40
    Cervix <5 20-30
    Pancreas <1 25-40
    Esophagus <1 20-35
    Stomach <1 20-35
    Ovary 5 10-25
    Hepatoma <1 20-60

  • Internationally: The incidence of pulmonary metastases reflects the prevalence of primary tumors in the Table, and no international variation is reported.

Mortality/Morbidity: The presence of pulmonary metastases is a bad prognostic factor that indicates disseminated disease. Mortality rates depend on the primary tumor.

  • Patients with carcinoma of the pancreas and bronchus who have pulmonary metastases have a 5-year survival rate of less than 5%.

  • One half of the patients with lymphangitis carcinomatosis die within 3 months.
  • By contrast, chemosensitive tumors, such as choriocarcinoma and testicular teratoma, have a much better prognosis.
  • An isolated pulmonary metastasis (eg, from colon or kidney) can be resected, with a 5-year survival rate of 50%.

Sex: The incidence of pulmonary metastases reflects the incidence of common primary carcinomas. Overall, the difference between males and females is not significant.

Age: Because the incidence of common tumors increases with patient age, the frequency of pulmonary metastases increases with patient age. However, pulmonary metastases are seen in children with tumors such as Wilms tumors.

Anatomy: Pulmonary metastases are common because the entire output of the right heart and the lymphatic system flow through the pulmonary vascular system.

The initial event occurs at the primary tumor site. Fragments of tumor are dislodged after venous invasion, and they are carried as tumor emboli via the systemic circulation to the lungs. Most of these fragments lodge in the small pulmonary arteries or arterioles, where they may proliferate and extend into the lung parenchyma and ultimately form nodules. Most commonly, these nodules are subpleural location or located in the lung bases rather than in the upper lung; these locations reflect the pulmonary arterial circulation.

Less often, tumor emboli remain confined to the perivascular interstitium and spread along the lymphatic channels toward the hilum or lung periphery. This is the mechanism in most patients with lymphangitis carcinomatosis. The second and less common mechanism is retrograde spread from hilar lymph nodes via lymphatic channels.

Clinical Details: As many as 90% of patients with lung metastases have a known extrathoracic primary tumor or symptoms of a synchronous primary tumor.

Symptoms are usually absent in patients with multiple metastases (80-95%). Dyspnea may develop as a result of parenchymal replacement by a large tumor load, airway obstruction, or pleural effusion. Sudden dyspnea is associated with the rapid development of a pleural effusion, pneumothorax, or hemorrhage into a lesion.

Although the lung metastases themselves may be asymptomatic, patients often have symptoms related to their primary tumor (eg, renal cell carcinoma, colorectal tumors, breast cancer). When lung metastases are discovered in patients with no symptoms suggestive of a primary site, clinically silent tumors such as pancreatic or biliary tumors should be considered.

Patients with lymphangitis usually have progressive dyspnea and a dry cough. Endobronchial metastases may result in wheezing or hemoptysis. Extension to the pleura may cause pleuritic pain, and an apical metastasis may result in Pancoast syndrome. Hypertrophic pulmonary osteoarthropathy is rare.

A pneumothorax associated with pulmonary metastases often indicates that an osteosarcoma is the primary site. As many as 5% of patients with these tumors may have a pneumothorax, which more commonly occurs during chemotherapy than at other times.

Preferred Examination: Chest radiography (CXR) is usually the first examination performed to detect pulmonary metastases. Also, metastases may be unexpectedly discovered at CXR examination.

CT has higher resolution than CXR. Compared with CXR, CT depicts more and smaller nodules.

High-resolution CT (HRCT) is the modality of choice for demonstrating the presence and extent of lymphangitis carcinomatosis.

Transthoracic biopsy and needle aspiration may be helpful in determining the nature of the nodule. Small tissue fragments can be compared with those of the known primary tumor. Transthoracic needle aspiration has a positive yield of 85-95% in the evaluation of pulmonary nodules. The yield is lower with lymphangitic tumor spread. Transbronchial biopsy or thoracoscopic wedge resection is usually required for the histologic diagnosis of lymphangitic tumor spread.

Sputum cytologic analysis findings of malignant cells or bronchial brushings may be positive in 35-50% of patients with pulmonary metastases. Cytologic analysis of any pleural fluid of malignant origin may yield positive results in as many as 50% of patients. Cytologic results usually do not distinguish primary and secondary malignant lesions. Renal and colonic metastases are the easiest to identify.

Bronchoscopy may be a useful examination in assessing metastases with endobronchial extension.

Limitations of Techniques: Many patients with a single pulmonary metastasis diagnosed by using CXR findings are likely to have more than one lesion.

CT findings are more sensitive than CXR findings in detecting the number of pulmonary metastases. CT scans depict many more lesions that are smaller than 10 mm in diameter.

The early stages of lymphangitis carcinomatosis are difficult to diagnose by using CXR; these are demonstrated best by using HRCT.

DIFFERENTIALS

Hamartoma, Lung
Histoplasmosis, Thoracic
Hodgkin Disease, Thoracic
Lung Cancer, Non-Small Cell
Lung Cancer, Small Cell
Lung, Carcinoid
Lung, Nontuberculous Mycobacterial Infections
Lung, Postprimary Tuberculosis
Pulmonary Hypertension
Sarcoidosis, Thoracic


Other Problems to be Considered:

The differential diagnosis of a solitary nodule includes benign lesions, such as hamartoma, granuloma (eg, tuberculosis, histoplasmosis, Wegener granulomatosis), pulmonary abscess, and infarct or focal fibrosis, and primary bronchial neoplasm.

The differential diagnosis of multiple nodules, which are more likely than single lesions to be metastases, includes granulomata, abscess, multiple infarcts, and sarcoidosis.

The differential diagnosis of lymphangitis carcinomatosis includes pulmonary edema and fibrosis.

 

X-RAY

Findings: Standard CXR is usually the initial test in the detection of pulmonary metastases. More lesions are detected with a high-kilovoltage technique (>125 kV) than with the standard technique.

Patterns of disease

Pulmonary metastases are usually multiple. They vary in size from 3 mm to 15 cm or more (see Images 1-6). Nodules of the same size are believed to originate at the same time, in a single shower of emboli. Rarely, numerous tiny nodules mimic the pattern of miliary tuberculosis (see Image 7). Nodules are found most commonly in the outer third of the lungs, especially in the subpleural regions of the lower zones.

Nodules smaller than 2 cm are often round and have smooth margins (see Image 6). Larger nodules, especially metastatic adenocarcinoma (see Image 1), are frequently lobulated and have irregular margins. They may become confluent with adjacent masses, resulting in multinodular masses.

Cavitation occurs in 4% of metastases and 9% of primary tumors. Cavitation most frequently occurs in squamous cell tumors, and it is more common in the upper lobes (see Images 8-9) than in the lower lobes. Multiple cavitating masses may be the result of nonmalignant causes, such as Wegener granulomatosis (see Image 10).

A pneumothorax associated with pulmonary metastases usually indicates that an osteosarcoma is the primary site. As many as 5% of these patients may have a pneumothorax, and this occurs more commonly during chemotherapy (see Image 11).

Calcification is seen in metastases from osteogenic sarcoma, synovial sarcoma, or chondrosarcoma (see Image 12). These tumors may mimic hamartomas or granulomas. Calcification can develop at the site of pulmonary metastases that appear to have vanished after chemotherapy, especially those in the testes.

Hemorrhagic metastases, with a halo of hazy opacity, are most often seen in choriocarcinoma, but also occasionally appear with other vascular tumors such as angiosarcoma or renal cell carcinoma. Metastases from teratoma of the testis may show complete fibrosis or necrosis after chemotherapy. Thin-walled air cysts are present at the site of a treated metastasis (see Images 13-14). These air cysts contain no viable tumor.

Solitary nodules

Solitary pulmonary metastases are uncommon and account for 2-10% of all solitary nodules. The primary lesions that are more likely than others to produce solitary metastases include the following: carcinoma of the colon, especially that of the rectosigmoid area, which accounts for one third of cases; osteosarcoma; carcinoma of the kidney, testicle, or breast; and malignant melanoma.

Usually, no reliable features that distinguish a solitary metastatic nodule from a primary pulmonary carcinoma are demonstrated on CXR or CT images. On HRCT scans, approximately one half of metastatic nodules demonstrate irregular margins. They may be round or oval, or they may have lobulated margins. Irregular margins with spiculation may be caused by a desmoplastic reaction or tumor infiltration into the adjacent lymphatics or bronchovascular margin. Among lesions in 54 patients with known colonic carcinoma and a solitary pulmonary nodule, 25 lesions were found to be metastases. In patients with only one nodule, as depicted on CXR images, several nodules were demonstrated on CT scans.

The distinction between a new primary tumor and metastasis has important prognostic and therapeutic implications. Resection of a solitary metastasis may be beneficial. The interval between the appearance of the initial tumor and the appearance of the solitary nodule is also relevant. An interval greater than 5 years in patients with osteosarcoma is more likely to be associated with a new primary tumor. However, pulmonary metastases may occur many years after the primary tumor is diagnosed in patients with carcinoma of the breast or kidney.

Lymphangitis carcinomatosis

Although any neoplasm can cause lymphangitic spread, tumors most commonly originate in the breast, stomach, pancreas, or prostate. They are also caused by primary pulmonary carcinoma, especially small cell carcinoma and adenocarcinoma. Lymphangitic spread is present in 35% of autopsies of patients with solid tumors. Associated pleural involvement is common.

Microscopically, malignant cells are readily seen in lymphatic cells and interlobular septa. Edema or a desmoplastic reaction can contribute to interstitial thickening. The typical radiographic pattern consists of thickened interlobular septa (5-10 mm or smaller) and bronchovascular markings of irregular contour (see Images 15-16). The pattern is more obvious in the lower zones. A nodular component from intraparenchymal extension may be associated and confined to one lobe or one lung. Hilar and mediastinal lymphadenopathy is present in 20-40% of patients, and pleural effusions are present in 30-50%. Early diagnosis may be difficult with CXR findings, which may be normal in 30-50% of proven cases.

Intravascular emboli

Intravascular emboli occur most commonly with hepatocellular carcinoma and adenocarcinoma of the breast or stomach. They may be associated with lymphangitis carcinomatosis. CXR findings may be normal. The differential diagnosis includes pulmonary hypertension resulting from thromboemboli.

Bronchial and tracheal metastases

Patients with bronchial and tracheal metastases may present with obstructive pneumonitis, wheezing, hemoptysis, and coughing. Tracheal metastases are rare.

Degree of Confidence: CXR images may often fail to depict lesions smaller than 7 mm, particularly lesions in the apices and bases and adjacent to the heart, mediastinum, and pleura. Compared with CT, CXR depicts fewer small metastases. A solitary metastasis demonstrated on a CXR image is often associated with additional smaller lesions on CT scans. CXR may fail to depict lymphangitis carcinomatosis.

False Positives/Negatives: Benign lesions, such as hamartoma, granuloma (tuberculosis, histoplasmosis, Wegener granulomatosis), pulmonary abscess, infarct, and focal fibrosis, may mimic a solitary metastasis, as can a primary bronchial neoplasm.

Benign nodules, such as granulomata, abscess, multiple infarcts, and sarcoidosis, may appear the same as metastases. Miliary metastases may appear identical to miliary tuberculosis.

Lymphangitis carcinomatosis may be mistaken for pulmonary edema and fibrosis. Pulmonary hypertension resulting from thromboembolic disease may mimic disease caused by intravascular emboli.


CAT SCAN

Findings: CT has become the modality of choice for the detection of metastatic tumor and for surgical planning and follow-up in patients with pulmonary metastases. Greater sensitivity results from the lack of superimposition of structures and the higher contrast resolution of soft-tissue nodules in the lung parenchyma. In particular, lesions in the apices and bases and those adjacent to the heart, mediastinum, and pleura may not be seen on CXR images; however, they are seen on CT scans.

Technique

CT has a greater sensitivity than CXR (or linear tomography, which it has replaced) in the detection of pulmonary metastases (see Images 17-20). Spiral CT is the method of choice because it allows scanning of the lungs without respiratory misregistration. Spiral CT scans depict more nodules than conventional CT scans, but spiral CT is less sensitive to the presence of calcium in the lesions.

Sensitivity can be increased by performing spiral CT and by spacing the scan reconstructions at 4- to 5-mm intervals rather than the standard 8- to 10-mm intervals. Further sensitivity can be achieved by using multisection CT.

HRCT is the technique of choice for evaluating lymphangitis. With HRCT, 1- to 2-mm-thick sections are obtained every 10 mm through the chest. Spatial resolution is maximized by the narrow collimation (1-2 mm) and high-resolution reconstruction algorithms.

Pulmonary nodules

CT scans can depict 3-mm nodules, but CXR rarely depicts lesions smaller than 7 mm. The increased sensitivity of CT is achieved at the cost of decreased specificity. Many of the additional small nodules revealed by CT scans are granulomatas and not metastases. Most lesions smaller than 7 mm cannot be characterized because they are not palpable at surgery, and they cannot be examined at biopsy. The specificity of CT depends on the type and stage of the primary malignancy and on the incidence of benign nodules in the population.

The following features are more likely to be associated with metastases than with benign disease: noncalcified lesions; spherical or ovoid lesions, rather than linear or irregular lesions; close relationship to an adjacent vessel; decreased attenuation distal to the nodule; and reticular changes around the nodule.

The growth of a nodule is also a reliable indicator. Doubling times of metastases range from 2-10 months.

Intravascular emboli are seen on histologic analysis, but they are usually not visualized on CT scans because they tend to occur in arterioles or small arteries. Rarely, they can be seen as beaded thickening of the peripheral arteries.

In highly vascular tumors such as angiosarcoma and choriocarcinoma, HRCT scans may depict a halo of ground-glass attenuation surrounding the metastatic nodules in rare cases.

Indications for CT

Indications for CT depend on the CXR findings, the likelihood that the underlying neoplasm has spread to the lungs, and the likely impact of the findings on treatment.

If CXR images demonstrate several metastases, CT scans are not required to show further metastases. If CXR findings are normal in patients with teratoma or osteosarcoma and without metastatic disease elsewhere, the discovery of pulmonary metastases may alter the patientís treatment. If CXR demonstrates a solitary metastasis, CT is indicated. If surgical resection of the pulmonary metastasis is being contemplated, CT is indicated.

CT scans are recommended every 3-6 months for 2 years in patients with high-risk tumors, bone and soft tissue sarcomas, testicular teratomas, and choriocarcinomas.

Lymphangitis carcinomatosis

Although any neoplasm can cause lymphangitic spread, the most common ones originate in the breast, stomach, pancreas, or prostate. Spread can also arise from a primary pulmonary carcinoma, especially small cell carcinoma and adenocarcinoma (see Images 23-26). Lymphangitic spread is present in 35% of autopsies of patients with solid tumors. Diagnosis may be difficult by using CXR because findings may be normal in 30-50% of proven cases.

HRCT is the imaging modality of choice. Smooth or nodular thickening of interlobular septa and peribronchovascular interstitium is present, with preservation of normal lung architecture (see Image 27). The nodular beaded septa seen in lymphangitis are not seen in pulmonary fibrosis or edema. Pleural effusions may be present in as many as 50% of patients with lymphangitis, and hilar and mediastinal lymphadenopathy may be present in 20-40%. Tumors in 50% of patients are asymmetric. Unilateral changes are common in patients with primary bronchial carcinoma (see Image 25). Rarely, spontaneous pneumothorax can complicate lymphangitis (see Images 28-29).

Degree of Confidence: CT findings are not specific and cannot help in distinguishing metastases and benign lesions, such as granulomas and pulmonary lymphoid nodules. The specificity of CT scans is higher in areas in which granulomata are uncommon.

The higher the sensitivity of CT (ie, multisection CT and spiral CT), the lower its specificity, because more benign nodules are detected, especially in regions of the world where histoplasmosis is endemic.

False Positives/Negatives: Nodules smaller than 3 mm are often missed on CT scans. False-positive results may be due to hamartomas, granulomas (due to tuberculosis, histoplasmosis, Wegener granulomatosis), sarcoidosis, silicosis, small infarcts, small areas of fibrosis, and intrapulmonary lymph nodes. Differentiation between metastases and benign lesions may be impossible.

 

MRI

Findings: Spin-echo MRI with a 0.35-T magnet can depict small nodules adjacent to vessels that often are missed on CT scans. Nodules near the diaphragm often are missed on MRI studies because of respiratory motion.

Among the various MRI sequences, short-tau inversion-recovery sequences have the highest sensitivity. False-positive findings are rare with CT, but they are not uncommon with MRI because of diaphragmatic motion, especially in the lower lobes. CT remains the imaging modality of choice.

ULTRASOUND

Findings: Ultrasonographic findings do not contribute to the diagnosis of pulmonary metastases.

 

NUCLEAR MEDICINE

Findings: Nuclear medicine studies are usually not used as primary imaging techniques in detecting pulmonary metastases.

Whole-body 2-[fluorine18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) performed for cancer staging can be used to detect pulmonary metastases, which appear as areas of increased metabolism.

In a small number of patients, FDG-PET studies had low sensitivity and specificity rates. Currently, FDG-PET is not considered superior to CT or MRI in the initial evaluation of suggested pulmonary metastases.

 

INTERVENTION

Intervention: Percutaneous biopsy or fine-needle aspiration may be used in select patients to confirm the nature of suggested pulmonary metastases.

Medical/Legal Pitfalls:

  • Failure to detect pulmonary metastases prior to radical excision of the primary tumor
  • Failure to plan and perform sequential follow-up imaging of the thorax in patients with a high risk of pulmonary metastases, such as teratoma of the testis and osteosarcoma

 

PICTURES

 

Caption: Picture 1. Large (cannonball) lung metastases from renal cell carcinoma.
Picture Type: X-RAY
Caption: Picture 2. Lung metastases from a low rectal carcinoma.
Picture Type: X-RAY
Caption: Picture 3. Pulmonary metastases from carcinoma of the breast. Note the right mastectomy and pleural effusion.
Picture Type: X-RAY
Caption: Picture 4. Multiple pulmonary metastases from an osteosarcoma.
Picture Type: X-RAY
Caption: Picture 5. Close-up view of pulmonary metastases (in the same patient as in Image 4). The right scapula had been excised because of an osteosarcoma.
Picture Type: X-RAY
Caption: Picture 6. Numerous pulmonary metastases from a carcinoma of the cecum.
Picture Type: X-RAY
Caption: Picture 7. Miliary shadowing due to pulmonary metastases.
Picture Type: X-RAY
Caption: Picture 8. Pulmonary metastasis from squamous cell carcinoma of the anus shows central cavitation.
Picture Type: X-RAY
Caption: Picture 9. Pulmonary metastasis from squamous cell carcinoma of the anus show central cavitation. This lateral view was obtained in the same patient as in Image 8.
Picture Type: X-RAY
Caption: Picture 10. Lung metastases. Cavitating masses due to Wegener granulomatosis.
Picture Type: X-RAY
Caption: Picture 11. Small right pneumothorax from pulmonary metastases due to Ewing sarcoma.
Picture Type: X-RAY
Caption: Picture 12. Calcification (arrowhead) in a pulmonary metastasis from a chondrosarcoma.
Picture Type: X-RAY
Caption: Picture 13. Pulmonary metastasis from a teratoma of the testis (in the same patient as in Image 14) after chemotherapy shows fibrosis or necrosis of the tumor.
Picture Type: X-RAY
Caption: Picture 14. Pulmonary metastasis from teratoma of the testis before chemotherapy.
Picture Type: X-RAY
Caption: Picture 15. Lung metastases. Lymphangitis carcinomatosa due to carcinoma of the prostate. Note the sclerotic bony metastases. (See also Image 16.)
Picture Type: X-RAY
Caption: Picture 16. Lung metastases. Detailed view of Image 15 shows lymphangitis carcinomatosa due to carcinoma of the prostate.
Picture Type: X-RAY
Caption: Picture 17. Solitary 10-mm pulmonary metastasis (arrowhead) from a renal cell carcinoma, which was not visible on chest radiographs.
Picture Type: CT
Caption: Picture 18. Multiple pulmonary metastases and pleural effusions from a carcinoma of the rectum.
Picture Type: CT
Caption: Picture 19. Pulmonary metastases are usually more numerous in the lower zones than in the upper zones. (See also Image 20.)
Picture Type: CT
Caption: Picture 20. Pulmonary metastases are less numerous in the upper zones. (Image obtained in same patient as in Image 19.)
Picture Type: CT
Caption: Picture 21. Pulmonary metastases from a carcinoma of the bronchus. (See also Image 22.)
Picture Type: X-RAY
Caption: Picture 22. Detailed view of Image 21 shows numerous small pulmonary metastases from a carcinoma of the bronchus.
Picture Type: X-RAY
Caption: Picture 23. Lung metastases. Unilateral lymphangitis carcinomatosa due to bronchial carcinoma in the right hilum. (See also Image 24.)
Picture Type: X-RAY
Caption: Picture 24. Lung metastases. Detailed view of Image 23 shows unilateral lymphangitis carcinomatosa due to bronchial carcinoma in the right hilum.
Picture Type: X-RAY
Caption: Picture 25. CT scan shows unilateral lymphangitis in a patient with bronchial carcinoma (in the same patient as in Image 23).
Picture Type: CT
Caption: Picture 26. CT scan demonstrates underlying bronchial carcinoma with narrowing of the right main bronchus (in the same patient as in Image 23).
Picture Type: CT
Caption: Picture 27. Lung metastases. High-resolution CT scan demonstrates irregular, coarse thickening of the interlobular septa due to lymphangitis carcinomatosa from a renal cell carcinoma. Note the bilateral pleural effusions.
Picture Type: CT
Caption: Picture 28. Lung metastases. Lymphangitis from breast carcinoma. (See also Image 29.)
Picture Type: X-RAY
Caption: Picture 29. Lung metastases. Lymphangitis from breast carcinoma. This right tension pneumothorax occurred 6 weeks after Image 28 was obtained. Note large left pleural effusion.
Picture Type: X-RAY