Lung Metastases Imaging

Pulmonary metastasis is seen in 20-54% of extrathoracic malignancies, [2] with the ungs being the second most frequent site of metastases from extrathoracic malignancies. Twenty percent of metastatic disease is isolated to the lungs. [2] The development of pulmonary metastases in patients with known malignancies indicates disseminated disease and places the patient in stage IV in TNM (tumor, node, metastasis) staging systems. This typically implies an adverse prognosis and alters the management plan. Imaging plays an important role in the screening and detection of pulmonary metastases. Imaging guidance is also used in histologic confirmation of metastatic disease. In patients with poor cardiorespiratory function and comorbidities, imaging-guided thermal ablation procedures are an effective alternative to surgical resection to improve survival. [1, 2, 6]

While a large number of patients with pulmonary metastases are asymptomatic at the time of diagnosis, some patients develop symptoms such as hemoptysis, cough, shortness of breath, chest pain, weakness, and weight loss. Patients with lymphangitic carcinomatosis present with respiratory dysfunction, including severe dyspnea. The most common pattern of pulmonary metastasis is the presence of multiple, well-defined nodules. Differential diagnoses for multiple pulmonary nodules include infections (eg, histoplasmosis, coccidioidomycosis in endemic areas, cryptococcal and nocardial infections as opportunistic infections in immunocompromised patients, septic emboli, abscess, paragonimiasis, hydatid), granulomatous diseases (eg, tuberculosis, sarcoidosis), and vascular/collagen-vascular diseases (eg, Wegener granulomatosis, rheumatoid arthritis).

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Chest radiography (CXR) is the initial imaging modality used in the detection of suspected pulmonary metastasis in patients with known malignancies. Chest CT scanning without contrast is more sensitive than CXR. For patients with bone or soft-tissue sarcoma, malignant melanoma, or head and neck carcinoma, CT scanning of the chest should be performed as an initial evaluation. In patients with primary renal or testicular cancer, chest CT scanning should be performed based on the presence of metastatic disease elsewhere. CT guidance is often required for obtaining samples from a suspected metastatic disease. Several thermal ablation options are available for treatment of pulmonary metastases, which is performed under CT guidance. [1, 2, 21, 39] CT is also used in assessing response to treatment. Small changes in tumor volume can be detected using volumetric techniques. [31]

Chest radiography may not identify small metastatic lesions and may underestimate the tumor burden. Dual-energy subtracted radiographs are more sensitive than conventional radiographs because of subtraction of overlying bony tissue. Computer-aided detection (CAD) has also been used for automatic detection of pulmonary nodules. Chest tomosynthesis is another low-dose technique with higher sensitivity that is used in the detection of lung nodules. CT scanning is more sensitive, but it has high rates of false positivity.

(See the images below.)

Pathophysiology

A majority of cancer-related deaths are attributed to metastasis rather than to localized primary tumor progression. However, the factors that regulate the premetastatic niche (PMN) and metastasis have not yet been clearly identified. [3] Malignancies can reach the lung through 5 different pathways—hematogenously through the pulmonary or bronchial artery, lymphatics, pleural space, airway, or direct invasion. [4]

The most common path is hematogenous spread, which occurs in cases of tumors that have direct venous drainage to the lungs. This includes cancers of the head and neck, thyroid, adrenals, kidneys, and testes, as well as malignant melanoma, soft-tissue sarcomas, and osteosarcoma. When the primary tumor invades the venous system, tumor cells embolize to the lungs through the pulmonary or bronchial arteries. Most of the tumor cells that reach the pulmonary capillary and arteriolar bed perish; however, some tumor cells pass through the vascular wall and develop parenchymal metastasis in the alveolar space or the interstitium.

Lymphatic spread is to the lungs, pleura, or mediastinum and occurs either in an antegrade fashion by lymphatic invasion through the diaphragm and/or pleural surfaces or by retrograde lymphatic spread from hilar lymph nodal metastasis. Lymphangitic spread refers to tumor growth in lymphatic channels, which are seen in the axial interstitium (peribronchovascular and centrilobular interstitium) and peripheral interstitium (interlobular septa and subpleural).

The tumor initially spreads via a hematogenous route to the pulmonary arterioles and capillaries, with retrograde spread from hilar nodal metastases or upper abdominal tumors, but subsequently extends through the vascular walls, invades the low-resistant peribronchovascular lymphatics, and spreads along the lymphatics. Lymphatic spread also occurs to the mediastinal lymph nodes through the thoracic duct, with subsequent retrograde spread to the hilar lymph nodes and then the lungs.

Spread within the pleural space can occur via pleural invasion by a local tumor, such as lung cancer or thymoma.

Endobronchial spread of tumor cells occurs with airway tumors. It is more common in primary pulmonary adenocarcinoma, less common in other types of lung cancer, and even less common in tracheobronchial papillomatosis.

Direct invasion of the lung occurs in tumors contiguous to the lung, including thyroid, esophageal, mediastinal, airway, and cardiovascular structures.

Rarer, atypical patterns of metastatic disease, including lepidic spread of metastatic malignancy along intact alveolar walls, have been reported and may mimic benign entities such as pneumonia or other malignancies such as primary pulmonary adenocarcinoma. Overlap of the imaging characteristics of these entities may complicate or delay diagnosis. Although classically associated with primary pulmonary adenocarcinoma, lepidic spread of metastatic malignancy along intact alveolar walls has been described in hepatocellular carcinoma and extrathoracic adenocarcinomas, including gallbladder, pancreas, stomach, small bowel, colon, ovarian, and malignant melanoma. [5]

Frequency

The venous return containing lymphatic fluid from body tissues flows into the lungs through the pulmonary vascular system; thus, all tumors have the potential to involve the lungs. Colorectal cancer (CRC) accounts for 9% of all cancers and is the third leading cause of cancer death in the United States. [6] Approximately 1 in 5 patients with CRC present with distant metastatic disease at diagnosis, and of the patients with CRC who develop systemic metastasis, 10-15% develop metastases to the lungs. [7] In addition to CRC metastasis, the lung is a common site of metastasis for other solid cancers (eg, bladder, breast, kidney, pancreatic, and prostate cancers). [2]

The lung is a common site of metastasis of colorectal cancer, which largely reduces patient quality of life and survival. The discovery of potential novel diagnostic biomarkers is highly meaningful for the early diagnosis of colorectal cancer with lung metastasis. [8]

Breast, colorectal, lung, kidney, head and neck, and uterus cancers are the most common primary tumors with lung metastasis at autopsy. Choriocarcinoma, osteosarcoma, testicular tumors, malignant melanoma, Ewing sarcoma, and thyroid cancer frequently metastasize to lung, but the frequency of these tumors is low.

Mortality & Morbidity

The presence pulmonary metastasis usually indicates advanced disseminated disease. Occasionally, tumor spread can be an isolated event. The mortality depends on the primary tumor; for example, in pancreatic and bronchogenic carcinomas, the 5-year survival rate in patients with pulmonary metastases is less than 5%. [2]

Early diagnosis is critical in planning effective therapy in patients who can be cured. Depending on several factors, metastasis can be resected, with 5-year survival rates up to 30-40%. [9]

Intervention

In specific circumstances, histopathologic samples are required from the lung lesion. A few such scenarios include (1) atypical imaging findings; (2) the development of a solitary pulmonary nodule in a patient with known malignancy; (3) pulmonary metastasis without a known primary source; and (4) assessment of response to therapy, particularly in nodules that are unchanged in size, but no positron emission tomography (PET) activity suggestive of sterilized metastasis.

Tissue sampling can be performed by transthoracic needle aspiration, transthoracic needle biopsy, transbronchial needle aspiration and biopsy, or minimally invasive video-assisted surgical methods.

Peripheral nodules are sampled using transthoracic aspiration/biopsy using CT guidance, provided they are not crossing major vascular structures or fissures. Central nodules and nodules involving airways are sampled using transbronchial needle aspiration and biopsy. Smaller nodules are now being sampled using state-of-the-art techniques such as electromagnetic-guided navigation bronchoscopy, usually with CT virtual bronchoscopic guidance. With an electromagnetic navigation system, a bronchoscopic probe sensor is placed within the electromagnetic field created around the chest. Real-time position is generated and superimposed on previously acquired thin CT images to navigate to the lesion.

Biopsy or fine-needle aspiration (FNA) is typically performed under CT guidance.

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The definitive treatment for pulmonary metastases from extrathoracic malignancies is surgical resection (pulmonary metastasectomy). Surgery is performed if the primary tumor is controlled, if no extrathoracic lesions are present, if it is technically resectable, and if general and functional risks are tolerable. [10] Only 15-25% of patients have lesions confined to the lung and are appropriate candidates for curative resection. For this reason, staging for metastatic disease outside of the lung is performed before pulmonary resection, by CT of the chest and abdomen, and, in selected cases, by PET scan and brain imaging with either MRI or CT scan. [11]

The 5-year survival rate for patients with CRC following pulmonary metastasectomy is 30-50%. Survival has been shown to be better in patients with fewer number of metastases. Other favorable pronostic factors include long disease-free interval and normal CEA levels. [10]

In patients who are not in adequate physical condition to undergo pulmonary metastasectomy, other options include stereotactic radiosurgery and thermal ablation procedures. Thermal ablation procedures induce coagulation necrosis of tumor cells and are typically performed with CT guidance. These include radiofrequency ablation (RFA), microwave ablation, laser ablation, and cryoablation. The primary goal of all tumor ablation procedures is to eradicate all the malignant cells along with a margin of normal tissue, while causing minimal damage to normal lung tissue. By doing this, adequate tumor control is achieved and survival is prolonged. The main advantage of thermal ablation procedures is selective and limited damage of lung tissue to minimally impact pulmonary function.

The ablation procedure can be repeated many times. In addition, ablation procedures can be performed regardless of previous therapy, even in patients who have adhesions from previous surgeries or radiation-induced pneumonitic changes. Because of this, ablation is often used as a salvage treatment for oligo-recurrence after surgery and radiation.

Thermal ablation is also not an obstacle for performing concurrent or adjuvant chemotherapy or adjuvant radiation therapy. In fact, if the tumor size is downgraded by thermal ablation, the remaining tumor cells may become more sensitive to chemotherapy. As a result, the combination of thermal ablation, along with chemotherapy and other modalities, can increase the efficacy of thermal ablation through synergistic and even additive effects.

Complications that can be seen during ablation procedures include pneumothorax, pulmonary hemorrhage, bronchopleural fistula, pulmonary artery pseudoaneurysm, systemic air embolism, injury of the brachial or phrenic nerve, pneumonia, needle-tract seeding of cancer, and deterioration of interstitial pneumonia. [12]

Radiofrequency ablation

RFA operates using alternating electrical current within the radiowave frequency (460-500 kHz). Using CT guidance, the RFA electrode is placed within the metastasis. Electrical current is concentrated near the noninsulated tip of the electrode, and the circuit is completed by returning to electrical ground pads in the patient’s thighs. The electrical current causes agitation of ionic dipolar molecules in the surrounding tissue and fluids. The heat is radially distributed to surrounding tissues, usually in an ellipsoid shape with predictable distribution.

RFA has been shown to improve survival in patients with pulmonary oligometastasis and oligo-recurrence, which means one or a few metastatic or recurrent lesions, without and with controlled primary tumor, respectively. Several studies have been performed using RFA on several cancers. Generally, a disease-free survival of 36 months or more is considered to indicate good response. [13]

In colorectal cancers, Hiraki et al demonstrated an overall survival rate of 96% at 1 year, 54% at 2 years, and 48% at 3 years. [12] Yamakodo et al demonstrated 46% at 3 years and median survival of 60 months. [14] An absence of extrapulmonary metastasis, small tumor size (< 3 cm), single lung metastasis, and normal carcinoembryonic antigen (CEA) value were good prognostic indicators.

In hepatocellular carcinoma, Hiraki et al demonstrated an overall survival of 87% at 1 year and 57% at 2 and 3 years. [15] Median and mean survival were 37.7 months and 43.2 months, respectively. Well-controlled primary cancer, an absence of intrahepatic recurrence, Child-Pugh class A, an absence of cirrhosis or hepatitis C infection, and an α-fetoprotein value of less than 10 ng/mL were good prognostic indicators.

In another study of renal tumors, overall survival in curative and palliative ablation groups were shown to be 100% and 90%, respectively, at 1 year; 100% and 52% at 3 years; and 100% and 52% at 5 years. [16]

Maximum tumor diameter is an important factor. In bone and soft-tissue sarcomas, 3-year survival rates were 65.2% in one study, with a median disease-free survival of 7 months. [17]

Microwave ablation

Microwave ablation is performed using microwave antennae and microwave generators with power settings of 35-45 W and an ablation time of 15±5 minutes under CT guidance. The efficacy of the treatment is determined by preablation tumor size and its location in relation to the hilum. The histopathologic nature of the primary tumor has no significant impact on the result of microwave ablation therapy.

Tumors smaller than 3 cm and peripheral lesions (ie, >5 cm from the hilum) fare better than larger and more central lesions. With hilar lesions, the presence of large adjacent pulmonary arteries results in a current-sink effect, which diverts the heat current during ablation away from the core of the tumor, resulting in cooling of the tumor. Solutions to this issue include using prolonged current application and multiple simultaneous antennae, but these are associated with a higher risk of complications such as hemorrhage.

Following microwave ablation, the initial CT scan may show increased tumor volume due to edema and an inflammatory response to heat energy. However, if the tumor size increases after 4-6 weeks, recurrence should be considered. Higher survival has been observed in patients with tumor-free states after successful ablation, as compared to patients in whom ablation has failed. [18]

Cryoablation

Cryoablation is performed using a cryoprobe with high-pressure argon and helium gases for freezing and thawing on the basis of the Joule-Thomson principle. Three freeze-thaw cycles are performed to freeze a tumor 2.5-3 cm in diameter.

Initial freezing causes an ice ball with a diameter of only 1 cm, since air prevents conduction of low temperature and there is not enough water in the lung parenchyma. However, after the first thawing, the induced massive hemorrhage excludes air and results in the formation of a larger ice ball in subsequent freezing steps. During thawing, the probe reaches a temperature of 20°C.

Cryoablation has been shown to result in 1- and 3-year progression-free intervals of 90.8% and 59%, respectively. The 3-year local progression-free interval of tumors smaller than 15 mm in diameter was 79.8% and of tumors larger than 15 mm was 18.6%. One-year and 3-year overall survival rates were 91% and 59.6%, respectively. [19]

Laser ablation

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Laser ablation is performed with a miniaturized, internally cooled applicator system, which has an optical laser fiber with a flexible diffuser tip. Nd-YAG laser generators are typically used. Laser ablation is performed with single or multiple applicators under CT guidance. Wattage can be increased at 2 W/min, and a maximum energy of 14 W has been maintained for 15 minutes. The total amount of energy per tumor has ranged from 7.4 to 68 W. Using laser ablation, definitive control of initial pulmonary disease has been achieved in 45% of patients, with 1-, 2-, 3-, 4-, and 5-year survival rates of 81%, 59%, 44%, 44%, and 27%, respectively. [20]

The advantage of laser ablation is the use of laser light and its comparably well-studied conduction in lung tissue. Use of thin-caliber applicators and flexible fibers is a major advantage, and the procedure is more cost-effective than other ablation techniques.

Imaging modalities

Imaging modalities available for evaluation of pulmonary metastasis include CXR, CT scanning, MRI, scintigraphy, and PET scanning. The preferred imaging modality depends on the biological behavior of the tumor, sensitivity and specificity of the imaging modality, radiation dose, and cost-effectiveness.

In a patient with known malignancy, CXR, with posteroanterior and lateral views, is usually the first imaging study performed to detect pulmonary metastases. Not uncommonly, metastases may be unexpectedly discovered on CXR performed for some other purpose. CXR performed with dual-energy subtraction has higher sensitivity in the detection of pulmonary metastasis by subtracting the overlying bones. Computer-aided detection (CAD) has been used in automatic detection of small pulmonary nodules. In a patient with known malignancy, if CXR demonstrates multiple pulmonary nodules, further imaging is usually not necessary, unless biopsy is planned or precise quantification of the metastatic burden is required before metastasectomy or as a baseline study to assess response following chemotherapy or radiation.

CT scanning is the most sensitive modality in the detection of pulmonary metastasis because of its high spatial and contrast resolution and lack of superimposition with adjacent structures, such as bones and vessels. [21, 22, 23] Compared to CXR, CT scanning can detect a larger number of nodules and nodules smaller than 5 mm. CT scanning can detect 3 times as many noncalcified nodules as CXR. [24] In addition, it can detect findings such as lymphadenopathy; pleural, chest wall, airway, and vascular involvement; and upper abdominal and bony findings that may alter management. In a patient with known malignancy, chest CT scanning is performed if CXR shows a solitary nodule; equivocal nodule; negative findings but the extrathoracic malignancy has high risk of lung metastasis (eg, breast, kidney, colon, bladder); or multiple nodules (but biopsy or definitive treatment by mastectomy, chemotherapy, and radiation is planned).

The radiation dose from frequent CT scans can be reduced by using several dose-reduction techniques such as low kV, low mAs, adaptive tube current modulation, and iterative reconstruction algorithms. The sensitivity of nodule detection can be increased by using postprocessing tools such as maximum-intensity projection (MIP) or volume rendering (VR). High-resolution CT (HRCT) scanning is used for detection of lymphangitic carcinomatosis. CT scan findings are not very specific, since nodules can be seen in a variety of benign conditions, including granulomas, hamartomas, and vascular abnormalities.

The American College of Radiology (ACR) recommended that CXR should be the initial imaging modality used in the screening of pulmonary metastasis in patients with known extrathoracic malignancy. CT scanning without intravenous contrast is more sensitive than radiography in the detection of pulmonary metastasis. For patients with bone and soft-tissue sarcoma, malignant melanoma, and head and neck carcinoma, CT scanning of the chest should be performed as the primary imaging modality. In patients with primary kidney or testicular cancers, chest CT scanning should be performed based on the presence of metastatic disease elsewhere. [2]

Bone and soft-tissue sarcomas

CT scanning is the first and preferred imaging modality for screening metastases, since aggressive resection of pulmonary metastasis is recommended for survival. Patients with 3 or more pulmonary nodules, bilateral nodules, or large nodules are more likely to have metastasis. Routine chest radiographs and CT scans are recommended for the first 5 years, with radiography at each visit, chest CT scanning every 3 months for the first year, chest CT scanning every 4 months for the second year, chest CT scanning every 6 months for third year, and chest CT scanning once yearly thereafter.

Renal cell cancer

Pulmonary metastasis is seen in 25-30% of patients at the initial diagnosis and in 30-50% at later stages of renal cell carcinoma. Resection of pulmonary metastasis has been shown to improve survival. CXR is the recommended initial screening modality. Chest CT scanning is indicated only for (1) a solitary pulmonary nodule, (2) symptoms of endobronchial metastasis, (3) extensive regional disease, and (4) the presence of other extrathoracic metastasis amenable to resection. CT scanning is not required if CXR shows typical multiple nodules or if CXR findings are normal in a patient with low-stage disease. Some authors advocate lifelong biannual CXR and CT scanning. [27]

Testicular cancer

CXR is the recommended primary imaging modality for patients with negative abdominal CT findings, and chest CT scanning is the recommended primary imaging modality for patients with an abnormal abdominal CT scan. This recommendation is based on studies that showed a direct correlation between abdominal CT and chest CT findings. For those with an abnormal abdominal CT scan, chest CT scanning detects 12.5% more nodules than that seen on CXR. For those with negative abdominal CT findings, chest CT scanning does not increase the yield over CXR. In fact, the false-positive rate in such patients is 2.3%, which results in unnecessary increased morbidity. [29]

Malignant melanoma

The need for chest CT scanning depends on the stage of the primary tumor. Metastasectomy may be the only potentially curative treatment modality in stage IV disease, regardless of the number of lesions. Chest CT scanning is recommended to evaluate the number of nodules and other associated disease. [2]

Head and neck carcinoma

Distant metastasis is seen in 5.5% of patients with head and neck cancers. In addition, the risk of synchronous malignancies in head and neck cancers is 15-30%. Chest CT scanning is an important screening examination for determining metastatic disease. Chest CT scanning has been shown to identify malignant lesions in 25.8% of these individuals, of which 15% have been shown to be pulmonary metastases, 5.4% are lung cancer, and 1.1% are esophageal cancers. [30]

Diagnostic studies

Histopathologic samples are often required for confirming the diagnosis of pulmonary metastasis and in select cases to identify the primary tumor. Samples can be obtained using CT-guided transthoracic biopsy or FNA cytology. The tissue fragments can be compared to those of the primary tumor.

Immunohistochemistry is helpful in identifying the primary tumor. Transthoracic needle aspiration has a positive yield of 85-95% in the evaluation of pulmonary metastasis, but the yield is lower with lymphangitic spread.

Transbronchial biopsy or navigational bronchoscopic biopsy is performed in central lesions. Occasionally, thoracoscopic wedge resection may be essential for histologic diagnosis. Extensive immunohistochemistry reveals a final diagnosis in 50% of patients. Additional information is provided by gene expression or reverse-transcription polymerase chain reaction (RT-PCR). [2]

Sputum cytologic analysis or bronchial brushings for malignant cells 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. Such analysis usually does not distinguish between primary and secondary malignant lesions; however, this can be performed for renal and colonic primary tumors. Additional workup includes hematologic studies such as complete blood cell (CBC) count and a basic metabolic panel (BMP), which may identify abnormalities possibly related to a paraneoplastic syndrome. [2]

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