Secondary Lung Tumors 

Updated: Feb 08, 2019
Author: Daniel S Schwartz, MD, MBA, FACS; Chief Editor: John Geibel, MD, DSc, MSc, AGAF 

Overview

Background

Secondary lung tumors are neoplasms that spread from a primary lesion. The primary tumor can arise within the lung or outside the lung, with the metastases traveling through the bloodstream or lymphatic system or by direct extension to reach their destination. The secondary tumors most typically appear as well-circumscribed, noncalcified nodules.[1]

These secondary cancers are identified by their site of origin. Thus, a colon cancer that metastasizes to the lung is still known as a colon cancer. In children, most lung cancers are secondary.[2]

Metastatic malignant neoplasms are the most common form of secondary lung tumors. Lung metastases are identified in 30-55% of all cancer patients, though prevalence varies according to the type of primary cancer. Benign neoplasms (eg, benign metastasizing leiomyomas) are uncommon exceptions.

In this article, the approach to secondary lung tumors is discussed, with an emphasis on clinical decision-making to determine whether tissue diagnosis would alter clinical management. Also discussed is the multidisciplinary approach to determine when continued systemic chemotherapy for metastatic disease should be accompanied by radiation, surgery, or both.

Almost any cancer has the ability to spread to the lungs, but the tumors that most commonly do so include bladder cancer, colon cancer, breast cancer, prostate cancer, sarcoma, Wilms tumor, and neuroblastoma. (Primary lung cancers most commonly metastasize to the adrenal glands, liver, brain, and bone.)[1]

Secondary lung tumor is a term that is also used for the malignancies that arise in the lungs as a consequence of therapy for cancer (eg, chemotherapy, radiotherapy, or bone marrow transplant).[3]  This article is not intended to cover the description of such tumors.

Spread to the lungs is usually the marker of an advanced malignant disease, but spread can also occur as an isolated early event. In certain circumstances, surgical resection with curative intent can be performed, with a reported 5-year survival rate of as high as 30-40%, depending on the underlying primary malignancy and the selection criteria for surgery.

Pathophysiology

The mechanisms through which cancer spreads to the lungs are direct extension and true metastatic spread through the bloodstream, airway, or lymphatic system. Iatrogenic implantation of a primary tumor is exceedingly rare.

Direct extension

Cancer spread through direct extension is not frequently encountered and most commonly includes direct invasion by a primary neoplasm, involving a contiguous organ or structure (eg, thyroid, esophagus, thymus, or chest wall), or spread from a neoplasm metastatic to another intrathoracic structure (eg, rib or mediastinal lymph node, commonly causing an obstructive lesion of the trachea or bronchus).

Direct extension can also occur through a vascular route, such as the spread of renal cell cancer or testicular germ cell cancer as a tumor thrombus to the lung via the inferior vena cava and the right side of the heart.

Metastatic spread

True metastases occur via the pulmonary arteries or bronchial arteries, via the pulmonary lymphatics, across the pleural cavity, or, infrequently, via the airways.

Arterial

The pulmonary arteries are the most common route for metastases. Cancers most likely to metastasize to the lungs include those with a rich vascular supply draining directly into the systemic venous system. Spread via bronchial arteries may be responsible for some endobronchial metastases. (Other proposed modes of endobronchial spread include bronchial invasion from parenchymal lesions, spread via involved mediastinal or hilar lymph nodes, and extension along the proximal bronchus.)

Lymphatic

Lymphangitic spread can occur in association with hematogenous dissemination, which is subsequently followed by invasion of the adjacent interstitium and lymphatics, with subsequent tumor spread toward the hila or toward the periphery of the lung.

Lymphangitic spread can also occur via retrograde spread of a tumor from the originally affected mediastinal or hilar lymph nodes, with consequent obstruction of lymphatic flow.

Pleural

Pleural spread most frequently results in pleural metastases in the caudal and posterior parts of the pleural cavities.

Airway

Spread via airways is rare and difficult to prove, except in the case of bronchoalveolar carcinoma.

Etiology

Although any cancer can metastasize to the lungs, the following neoplasms are most likely to do so:

Prognosis

Lung metastases commonly cause no symptoms, but in some cases they can be the major cause of morbidity. Symptoms include hypoxemia, dyspnea, cough, and hemoptysis. Hypoxemia and dyspnea are most commonly observed in patients with lymphangitic spread, and cough and hemoptysis are associated with endobronchial metastases. Palliative care to address symptoms or local treatment with curative or palliative intent may be indicated.

The presence of hypoxemia cannot be explained by a cancerous process in the absence of lymphangitic spread, major lung collapse, or massive pleural effusion. Thus, it is usually a finding in patients with advanced disease. The presence of hypoxemia in the absence of these conditions should prompt the search for causes such as the following:

The presence of metastasis indicates an advanced stage of the malignant process. In certain circumstances, however, depending on the underlying primary malignancy and the selection criteria for surgery, surgical resection with curative intent can be performed, with an expected 5-year survival rate of 30-40%.

The following 5-year survival rates have been reported after resection of single pulmonary metastasis of the metastatic cancers known to respond favorably to surgical treatment:

  • Adenoid cystic carcinoma - 63%
  • Testicular cancer - 60%
  • Squamous cell carcinoma (SCC) of the head and neck - 40-50%
  • Colon cancer - 40%
  • Breast cancer - 30-50%
  • Soft-tissue sarcomas - 38%
  • Renal cell cancer - 30-35%
  • Osteogenic sarcoma - 20-57%

Solitary lung metastasis has a significantly better prognosis than does metastasis at any other visceral site in metastatic malignant melanoma, with a median survival of 8.3 months and a 5-year survival rate of 4%. The other important independent outcome predictor in metastatic malignant melanoma is the disease-free interval prior to the identification of metastatic disease (< 12 months vs >12 months).

 

Presentation

History

Patients with multiple pulmonary nodules as a result of metastatic spread can be asymptomatic, especially those with indolent, slow-growing cancers, such as papillary thyroid cancer or adenoid cystic carcinoma of the salivary gland. However, the clinical presentation of patients with pulmonary metastatic lesions occurring late in the course of advanced extrapulmonary cancer is commonly dominated by the signs and symptoms of advanced/terminal malignant disease and by signs and symptoms associated with the primary cancer.

Lymphangitic spread of the cancer into the lungs is associated with the recent onset of rapidly progressive dyspnea at rest and, occasionally, dry cough. This pattern is usually encountered in patients with a known history of cancer, most commonly of the breast, stomach, pancreas, or prostate.

Endotracheal and endobronchial metastases can be associated with new-onset cough, shortness of breath, and, occasionally, hemoptysis and chest pain.

Physical Examination

Upon physical examination, signs of atelectasis, postobstructive pneumonitis, or postobstructive airtrapping can be evident. However, most patients are asymptomatic.

Solitary pulmonary nodules occupying the single site of distant metastatic spread is frequently the presenting finding in patients with secondary lung tumors, and patients with this type of spread are most commonly asymptomatic. This presentation is particularly common in renal cell cancer, Wilms tumor, testicular cancer, and sarcomas, but the finding of a solitary nodule is not specific and can be observed in any type of cancer.

Aside from secondary lung tumors, the differential diagnosis of discrete masslike lesions of the lung that appear in a patient with a known primary tumor includes unrelated primary malignancy (so-called synchronous second primary tumor) and benign neoplastic or nonneoplastic lesions.

 

DDx

Diagnostic Considerations

The finding of a solitary pulmonary nodule is not specific, and the differential diagnosis includes any type of cancer and a number of nonmalignant etiologies.

Multiple pulmonary nodules of cannonball appearance are associated with colorectal cancer and sarcoma. Thyroid cancer and ovarian cancer are more commonly associated with a miliary pattern. Both types of pulmonary nodules are associated with renal cell cancer and melanoma.

Endotracheal and endobronchial metastases are more likely to be found in patients with breast cancer, colorectal cancer, pancreatic cancer, renal cell cancer, and melanoma. Isolated airway metastases are considered rare; 6.3% of all endobronchial malignant lesions observed by bronchoscopy are metastatic tumors.

Autopsy series reported macroscopic involvement of the trachea and bronchi in 19-51% of all carcinomas metastatic to the lungs. The mean time from excision of the primary tumor to diagnosis of the endobronchial metastasis is 33.9 months (range, 9-156).

The cancers most commonly associated with lymphangitic spread into the lungs include breast cancer, stomach cancer, pancreatic cancer, prostate cancer, and lung cancers, particularly small-cell cancer and adenocarcinoma.

 

Workup

Approach Considerations

Secondary lung tumors may be identified when patients are evaluated for symptoms such as chest pain, dyspnea, cough, or hemoptysis or when patients with known primary tumors are being staged for metastases.

A clinical scenario that is not infrequently encountered is an incidental finding of secondary lung cancer of unknown origin, known as adenocarcinoma of unknown primary (ACUP), when patients are undergoing screening chest radiography, computed tomography (CT), or positron emission tomography (PET) with CT.

Radiographically, secondary lung tumors can manifest as discrete nodules (single or multiple), interstitial infiltrate(s), or endobronchial lesions with or without distal atelectasis or postobstructive pneumonitis. They often have a characteristic round appearance on chest radiographs.[4]

Diagnostic strategies for ACUP after the initial clinical and radiologic stepwise evaluation include extensive immunohistochemistry, which may yield a final classifying diagnosis in up to 50% of patients, followed by gene expression (or reverse transcription–polymerase chain reaction [RT-PCR]), which may then be expected to provide additional classifying information in the remaining patients.[5, 6, 7, 8]

The clinical decision to pursue tissue diagnosis depends on whether confirmation of clinical findings would alter treatment. Treatment of secondary lung tumors can be performed for curative intent, to reduce or eliminate tumor burden, or to palliate disease.

Laboratory Studies

The usual preoperative laboratory workup of any thoracic patient should include a coagulation profile consisting of a platelet count, international normalized ratio (INR), and activated partial thromboplastin time (aPTT). A complete blood count (CBC) and electrolyte count should also be performed, to screen for any hematologic derangements such as anemia or electrolyte abnormalities (eg, hypokalemia) that could impact anesthesia.

Cancer-specific tumor markers

Follow-up of cancer-specific tumor markers in serum is rarely clinically useful for diagnosis or prognosis. Examples of tumors in which serum markers can help to increase the specificity of imaging studies for establishing the diagnosis of pulmonary metastases include the following:

  • Nonseminomatous testicular germ cell tumors - In which the elevated levels of alpha fetoprotein and/or the beta subunit of human chorionic gonadotropin can help to predict tumor recurrence
  • Well-differentiated papillary or follicular thyroid cancer - By identification of elevated thyroglobulin levels
  • Prostate cancer - In which any detectable prostate-specific antigen in the serum after initial treatment suggests persistent disease or recurrence

Chest Radiography

Chest radiography using high-quality posteroanterior and lateral radiographs remains the most common imaging study in the initial staging evaluation of lung cancer patients. However, because of poor yield, it is rarely recommended as a part of the initial workup for common cancers (eg, breast cancer and colon cancer) at an early stage.

This is reflected by the observation that lung metastases have been detected with radiography in only 0.1% of the patients with stage I breast cancer. Chest radiographs are limited by the potential to overlook lesions located in the lung apices or posterior sulci or against the heart or mediastinum and by their overall poor sensitivity for lung nodules of less than 1.6 cm in diameter (far lower sensitivity than that of CT).

Overall, approximately 25% of the total lung volume is not readily accessible for visual examination with plain posteroanterior chest radiography.

However, recognition of secondary pulmonary tumors has increased with advances in this modality. Improvements in technique, including the use of Advanced Multiple Beam Equalization Radiography (AMBER) and a digital slot-scan charge-coupled device (CCD) system, have increased the utility of this simple and inexpensive staging modality.

Kroft et al showed that AMBER and CCD digital film systems were equivalent in detecting phantom nodules in or around the mediastinum (135/288 [46.9%] and 128/288 [44.4%], respectively). Both of these technologies were superior to older Bucky screen film technology (65/288 [22.6%]).[9]

However, other studies, using chest CT as the criterion standard, failed to confirm that these techniques had a significant advantage over standard chest radiographs.[10]

Computed Tomography

Since the introduction of CT in the 1970s, remarkable advances have been made not only in clinicians’ ability to diagnose lung cancer but, more important, in clinical staging. CT can define the location, size, and anatomic characteristics of a tumor far better and more precisely than chest radiography can,[10]  and it is used to delineate the locoregional extent and distal spread of a lung tumor.

The major advantages of CT are related to its axial format, higher-density resolution, and wider dynamic range. Continuous technical improvements and the development of more powerful and faster computers are responsible for the fact that current CT examinations of the chest produce a large amount of detailed imaging information in a very short time. Because of this evolution in technique, the development of new therapeutic strategies for lung cancer, and the introduction of PET, the contribution of CT to the staging of patients with lung cancer has been fluid.[11]

The identification of smaller lesions with CT offers the opportunity for improved diagnosis and earlier treatment of metastatic disease, which are likely to be beneficial. However, the magnitude of benefit has not been clearly documented by the literature. The increased sensitivity of CT has also resulted in an increased frequency of identification of nonmalignant lesions, which must be distinguished from true malignancies.

Sensitivity and specificity

Conventional CT of the chest from the level of the superior thoracic aperture to the adrenal glands is superior to plain chest radiography for the detection of pulmonary nodules and mediastinal lymph node involvement. Spiral (helical) CT further increases the odds of detecting pulmonary nodules.

Increased sensitivity comes at the cost of somewhat decreased specificity in comparison with standard chest radiography (posteroanterior and lateral) and conventional CT. However, the specificity of a test is strongly influenced by clinical circumstances. Thus, in highly selected patients (eg, those with osteogenic sarcoma or soft-tissue sarcoma, which are tumors that have a high propensity for metastasizing to the lungs), 95% of nodules on the CT scan have been shown to represent metastases.

Technetium-99m (99mTc)-labeled somatostatin analogue depreotide single-photon emission CT (SPECT) is used for evaluation of pulmonary nodules and staging of lung cancer, with reported sensitivity and specificity comparable to those of PET.

Indium-111 (111In)-labeled somatostatin analogue octreotide scanning is recommended for localization of carcinoid tumors. Whole-body iodine-131 (131I) scanning is recommended for the diagnosis of metastatic thyroid cancer.

Metastases vs benign lesions and primary cancers

In a patient with a known extrathoracic malignancy and a solitary pulmonary nodule on CT, various scenarios to identify metastatic lesions have been proposed.

With a history of sarcoma or melanoma, the pulmonary nodule is more likely to be a metastasis. In the case of underlying head and neck cancer or breast cancer, a second primary cancer in the lung is more likely. With other malignancies, the nodule is equally likely to be a primary lung cancer or metastatic disease.

Malignant lesions account for 3-10% of CT-detected pulmonary nodules. In an older patient, a solitary nodule is more likely to be malignant (lung cancer, in particular); in a younger patient, multiple nodules are more likely to be metastases. However, the number of pulmonary nodules is generally not helpful in distinguishing between benign and malignant lesions.

Generally, the larger the nodule, the more likely it is to be malignant (80% of solitary nodules >3 cm in diameter were malignant, compared with 20% of nodules < 2 cm), though autopsy data show that 57% of all metastases are 1-5 mm in diameter. Most of the nodules resected at the time of thoracotomy but not seen on a CT scan are small, fibrous lesions.

The mass-vessel sign (ie, a vessel entering the medial aspect of a discrete nodule) indicates hematogenous metastasis. Irregular nodule margins indicate a poor prognosis. An ill-defined margin is observed in choriocarcinoma and in other cancers after chemotherapy, indicating hemorrhage.

Calcification, cavitation, and doubling time

Calcified pulmonary metastases are observed with osteogenic sarcoma, chondrosarcoma, synovial sarcoma, ovarian cancer, breast cancer, colon cancer, and thyroid cancer. Cavitation occurs in pulmonary metastases of sarcomas and squamous cell carcinoma, as well as after treatment.

Patterns of calcification strongly suggestive of a benign nature of a nodule are diffuse homogenous calcification, central calcification, laminated concentric calcification, and popcorn calcification.

A doubling time of between 20 and 400 days is consistent with a malignant lesion. Doubling of the volume means that a nodule 0.5 cm in diameter increases by 0.12 cm in diameter, a 1-cm nodule increases by 0.26 cm in diameter, a 2-cm nodule increases by 0.52 cm in diameter, a 3-cm mass increases by 0.78 cm in diameter, and so forth.

Absence of any changes in size over a 2-year follow-up period is generally accepted as evidence of the benign nature of the nodule. Thin-section CT with three-dimensional (3D) reconstruction of the nodule is a particularly accurate method for assessing size changes.

Lymph nodes

Mediastinal nodes are considered positive on CT on the basis of size criteria—namely, whether the short axis is 1 cm or greater. Nineteen percent of nodes from 0.5-1 cm have been reported positive for micrometastases. Seventy-five percent of lymph nodes with cancer involvement are 1 cm or greater in diameter.

High-resolution CT is the imaging procedure of choice for lymphangitic carcinomatosis. Characteristic findings include thickened septal lines, prominent reticular patterns, nodular thickening of bronchovascular bundles, polygonal lines, and beaded septa. Hilar or mediastinal lymphadenopathy, lung masses, and lung nodules are also commonly identified.

Compared with sarcoidosis (a model of benign interstitial lung disease), lymphangitic carcinomatosis is more commonly unilateral or markedly asymmetric and is associated with fewer nodules and less distortion of surrounding lung parenchyma.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) of pulmonary pathology offers little improvement over CT, with a few exceptions. MRI is often superior to other imaging modalities in the investigation of paravertebral tumors and superior sulcus tumors. In paravertebral tumors, imaging of the spinal canal without contrast media is possible. The use of routine MRI for all lung cancer is probably superfluous and not cost-efficient. MRI should be reserved for times when local tumor invasion of the mediastinum, thoracic inlet, or paravertebral region is questioned on CT.[12]

Positron Emission Tomography

PET is a physiologic imaging modality that is fundamentally based on the detection of positrons emitted by isotopes of atoms with low atomic weights. Fluorodeoxyglucose (FDG), a D-glucose analogue, is the compound most commonly used for PET. It is a D-glucose labeled with positron-emitting fluorine-18 (18F). Cells take up and phosphorylate FDG as if it were glucose. However, FDG is not metabolized further and tends to accumulate intracellularly.[13]

In general, malignant cells have a higher rate of glucose metabolism than normal cells do. Thus, the intracellular accumulation of FDG, coupled with the preferential accumulation of glucose or its analogue in malignant cells, leads to the visualization of malignancies on PET.

PET is currently used as a diagnostic and staging tool in cancer. In particular, PET is being applied to staging lung cancer.[14]  This modality has a high likelihood of assessing the malignant potential in a pulmonary nodule, particularly if the nodule is solid and larger than 1 cm in diameter. A standard uptake value of greater than 3 is sensitive and specific for cancer.[15]

Limitations of PET include an inability to detect brain metastases, false-negative results in diabetic patients and in patients with malignant lung nodules less than 1 cm in diameter (size has not been shown to play a role in the detection of mediastinal lymph node metastases), and false-positive results in persons with granulomatous or inflammatory diseases. Cost remains an important consideration in ordering this test.

Metabolic imaging of the lungs, such as with PET, is now widely used in clinical practice. The ultimate aim of various advances in lung cancer imaging is to enable clinicians to distinguish between malignant and nonmalignant lesions without the need for tissue sampling. This goal has not yet been achieved. However, these newer imaging modalities play an increasingly important role in clinical decision-making algorithms, research, and drug development.[14, 15, 16]

Accuracy

In a study of 138 patients with hepatocellular carcinoma, Lee et al found that FDG-18 PET and CT together were extremely useful in detecting lung metastases larger than 1 cm, as well as bone metastases. PET had a 92.3% detection rate for secondary pulmonary nodules of 1 cm or greater, but only a 20% detection rate for lung metastases smaller than 1 cm.[17]

The investigators also found that chest CT was significantly more accurate than PET in detecting lung metastases and that PET was significantly more accurate than bone scanning in detecting bone metastases.

Whole-Body PET (Oncologic PET-CT)

The fusion of CT and PET (integrated CT-PET ) is now widely available and is very commonly used in clinical practice. Integrated CT-PET has been shown to be superior in anatomic localization and metabolic characterization of lesions as compared with CT alone, with PET scanning alone, or with using CT and PET and visually correlating the abnormalities.[18]

Types of PET-CT scanners

The terminology for PET-CT software and hardware can be confusing. The three primary modalities of PET-CT scanners are hybrid, fusion, and visually correlated. The hybrid, or integrated, PET-CT scanner creates two images, with one relying on CT and the other on PET. A computer then merges the two scans into a single image. This is the most accurate and specific system to date for the staging of non-small cell lung cancer (NSCLC). It is more expensive than PET, CT, or fusion software alone.

Fusion PET-CT scanners use software to create a 3D model of the CT study and a 3D model of the PET study; the scanners then use an algorithm to compare and provide an overlay of the images. This modality is less costly than hybrid PET-CT, but it may not be as accurate as integrated PET-CT for NSCLC.[19]

With fusion software, the CT and PET scans may be obtained on different dates; however, this increases the artifact, because there is different positioning, respiration, and other movement between scans. The fusion software can also be used with MRI.

With visually correlated PET-CT, the radiologist visually and manually compares CT and PET scans side by side. The examinations can be performed on different dates or at different facilities; however, this modality has been shown in several studies to be far less accurate.[19, 20]

False positives/negatives

With any PET-CT modality, the clinical stage often differs from the pathologic stage, meaning that significant false positives and negatives remain. The value of PET-CT scans is that they help to direct the surgeon toward targets for biopsies to rule out nodal or systemic disease. All suspicious areas should be biopsied, but the practice of using a positive PET or PET-CT scan as definitive evidence of cancer is absolutely wrong.

Staging

PET-CT has enhanced the ability to spatially identify structures that could more accurately evaluate the stage, as well as the individual T, N, and M status, in patients with NSCLC.[13, 21]

Only FDG-18 is currently used in PET-CT scans, but new radiopharmaceuticals and the prospects for developing other new radiotracers for imaging seem to be promising.[22]  As before, any new radiotracer must be carefully assessed to determine its accuracy at each nodal station and at each metastasis site.

In a retrospective study of 50 patients with lung lesions suspicious for cancer, integrated CT-PET correctly predicted T status in 86% of patients, N status in 80% of patients, M status in 98% of patients, and TNM status in 70% of patients. In comparison, correct prediction rates with CT alone were lower, reaching 68%, 66%, 88%, and 46%, respectively. With PET alone, the correct prediction rates were 46%, 70%, 96%, and 30%, respectively, and with visually correlated CT and PET scans, the correct prediction rates were 72%, 68%, 96%, and 54%, respectively.

Mediastinoscopy

Mediastinoscopy is the criterion standard for the diagnosis of mediastinal lymph node metastatic disease. Reported specificity of the procedure is as high as 100%, with a sensitivity of approximately 90%.

Cervical mediastinoscopy by the Carlens method is used for the diagnosis of right-side paratracheal, precarinal, and subcarinal lymphadenopathy. Left-side parasternal mediastinoscopy is used for the diagnosis of anterior mediastinal and aortopulmonary window lymph node metastases.

Mediastinoscopy is an outpatient procedure with a reported complication rate of 2% and a procedure-related mortality of 0.2%.

Aspiration and Biopsy

Transthoracic needle aspiration biopsy

Transthoracic needle aspiration (TTNA) biopsy remains the initial procedure for the diagnosis of pulmonary nodules.

A 1999 meta-analysis of 48 studies reported a pooled sensitivity for malignant lesions of 86.1% (range, 83.8-88.4%), with a pooled specificity of 98.8% (range, 98.4-99.2%).[23]  CT-guided TTNA biopsy was more sensitive than fluoroscopy-guided TTNA biopsy, though other factors are used to determine which procedure is more suitable for an individual patient. Also, aspiration biopsy needles were shown to yield better results than cutting needles.

Other authors consider bronchoscopy and TTNA biopsy to be complementary procedures and advocate their sequential use. TTNA biopsy has been reported to have a high yield for malignant nodules after an indeterminate bronchoscopy.

Pneumothorax is the most consistently reported complication of the procedure. The meta-analysis reported a pooled rate of 24.5% (range, 3.1-41.7%). The pooled rate of pneumothorax requiring chest tube drainage was 6.8% (range, 0-16.6%). Bleeding of varying severity, air embolism, myocardial infarction, and local iatrogenic spread of the tumor have also been reported following the procedure.

Transbronchial needle aspiration

Bronchoscopy with transbronchial needle aspiration (TBNA) for mediastinal lymphadenopathy or peripheral lung lesions, forceps biopsy, brush biopsy, brush-needle biopsy, bronchial aspirate, bronchial washing, or bronchoalveolar lavage (BAL) is used for the diagnosis of endobronchial tumor, lymphangitic cancer, and pulmonary nodule(s), with decreasing order of yield.

The overall yield of noninvasive bronchoscopic specimens (ie, bronchial aspirates, bronchial washings, BAL) for diagnosis of peripheral lesions is just less than 50%. The highest yield of BAL is in lymphangitic carcinomatosis.

The diagnostic yield of fiberoptic bronchoscopy depends on the lesion location and size, the character of the border, and the ability to perform all sampling methods. Diagnostic yield for lesions less than 2 cm in diameter is 54%, compared with 80% for those more than 3 cm in diameter. For lesions located in the lower-lobe basilar segments or in the upper-lobe apical segments, yield is 58%, compared with 83% for other locations, and for lesions with sharp borders, the yield is 54%, compared with 83% for lesions with fuzzy borders. Only one of the sampling methods was positive in 24% of bronchoscopies.

The overall yield of invasive bronchoscopic specimens for diagnosis of peripheral lesions is 52% for brush, 57% for transbronchial biopsy, and 51% for transbronchial needle aspiration.

TBNA with PET

Combining TBNA with PET has been shown to obviate the need for mediastinoscopy for mediastinal staging of non-small cell lung cancer with mediastinal lymphadenopathy in most patients.

In a retrospective study of patients with enlarged mediastinal lymph nodes, the combination of TBNA and PET demonstrated higher sensitivity, negative predictive value, and accuracy than did either modality alone. The study used histopathology by surgical lymph node dissection as the criterion standard and found that the combined TBNA and PET scan had 100% sensitivity, 94% specificity, 79% positive predictive value, 100% negative predictive value, and 95% accuracy in the detection of malignant lymph nodes. For PET alone, these rates were 68%, 89%, 46%, 95%, and 86%, respectively; for TBNA alone, these rates were 54%, 100%, 100%, 91%, and 92%, respectively.

Electromagnetic navigation bronchoscopy with biopsy

This uses technology that allows the operator to approach a peripheral lung mass using electromagnetic navigation (EMN) based on virtual bronchoscopy and real-time 3D CT images. The technology has been shown to be capable of reaching peripheral lung masses beyond the reach of the standard bronchoscope in an animal model.[24]

However, a multicenter study by Ost et al, using data from the AQuIRE (ACCP [American College of Chest Physicians] Quality Improvement Registry, Evaluation, and Education) registry to measure and identify the determinants of diagnostic yield for bronchoscopy in patients with peripheral lung lesions, found that EMN had a lower-than-expected yield.[25]  

Endobronchial ultrasonography with biopsy

Endobronchial ultrasonography (EBUS) has been widely adopted by pulmonologists and thoracic surgeons and is poised to replace mediastinoscopy in the future. For thoracic surgeons, the technique can be easily learned, and it may be important to do so to maintain its traditional and important role in the diagnosis and staging of thoracic malignancies.

EBUS has been associated with a low (< 1%) rate of serious adverse effects, and the procedure is touted as being highly accurate, with reported false-negative rates in the range of 6-9%. The aforementioned study by Ost et al found radial EBUS to have a lower-than-expected yield in patients with peripheral lung lesions.[25]

EBUS-guided fine-needle aspiration (FNA) biopsy of mediastinal nodes offers a less invasive alternative for histologic sampling of the mediastinal nodes.

Esophagoscopy with ultrasonographically guided needle aspiration

Esophagoscopy with ultrasonographically guided needle aspiration of accessible lymph nodes is an alternative to TBNA of lymph nodes accessible from the esophagus. It appears to be complementary to EBUS.[26]

Video-assisted thorascopic surgery with biopsy

Video-assisted thoracoscopic surgery (VATS) with lung biopsy is an inpatient procedure with a high diagnostic yield and a low complication rate. It can also be used for curative resection.

Immunohistochemistry and Gene Expression

Immunohistochemistry

The combination of a stepwise approach, with initial clinical and radiologic evaluation and a biopsy procedure, followed by histologic evaluation with extensive immunohistochemistry, may yield a final classifying diagnosis in up to 50% of patients who have not been otherwise diagnosed.[5]

Gene expression

In the remaining patients who have not been otherwise diagnosed, further classification based on gene expression may be expected to provide additional classifying information.[27, 28, 29]

The other approach would be a rather simultaneous method in which the gene expression profile is determined up front. Complete replacement of histologic and immunohistochemical evaluation by these methods has been suggested. Both strategies may have pros and cons in terms of accuracy, time frames, and costs. 

 

Treatment

Approach Considerations

Surgical treatment of secondary lung tumors should be considered for a pulmonary metastasis of primary lung cancer and, infrequently, for metastases of other types of primary cancer.

Surgical resection of a lung metastasis should not be performed unless, as indicated by predictive postoperative pulmonary function testing or cardiopulmonary exercise testing, the procedure has a significant likelihood of being curative and not disabling.

A metastatic nodule in the same lobe as a primary lung tumor was once considered a T4 tumor, as designated in the 1997 tumor-node-metastasis (TNM) classification scheme of the American Joint Committee on Cancer (AJCC) and the Union for International Control of Cancer (UICC). In the revised seventh edition of the TNM staging system, however, it was classified as a T3 lesion instead[30] ; the same was true in the eighth edition.[31]

According to the 1997 classification, the presence of two malignant nodules of the same histologic type in two different lobes on the ipsilateral side of the lung indicated metastatic disease or stage IV lung cancer. According to the seventh and eighth editions of the staging system, however, this was indicative of potentially resectable T4 lesions.[30, 31]

In both cases, surgical management that is more aggressive than is otherwise recommended for the same stage of the disease has been advocated. Every effort should be made to document the diagnosis of both individual nodules if they are located in different lung lobes, because the approach is more aggressive if two separate synchronous lung cancers are documented. (Synchronous lung cancers are staged separately, but the overall prognosis is poorer than for a single lung cancer of a similar stage.) This becomes particularly important if one the lesions proves benign.

Surgical Resection

Primary cancers

Surgical procedures of choice for the treatment of primary lung cancer tend to be lobectomy or pneumonectomy, depending on the size and the location of the tumor. Surgical decisions are also dictated by the involvement of regional lymph nodes. Meticulous evaluation of preoperative lung function with pulmonary function testing (PFT), possibly pulmonary perfusion scanning, and possibly cardiopulmonary exercise testing (CPET) is crucial in the marginal group of patients.

Surgery is also indicated for patients with selected primary extrapulmonary cancers in which the lung is identified as the sole site of metastatic disease and in which alternative therapy alone would not likely be effective, provided that the patient is otherwise able to tolerate the required lung resection. Favorable outcomes have been reported in cases of resection of multiple lung nodules for select tumors.

Metastasectomy

The procedure of choice for the treatment of secondary lung tumors is metastasectomy (wedge resection of the malignant nodule) by means of thoracotomy or video-assisted thoracoscopic surgery[32] (VATS). In the case of bilateral metastasis, median sternotomy may be preferable to staged thoracotomy, particularly if VATS is contraindicated. Surgical resection of pulmonary metastasis is always performed with curative intent.

Some authors believe that a thoracotomy is preferable to VATS, solely because, they reason, tactile evaluation is important to the resection of all metastatic disease.[33]  It can be counterargued, however, that the efficiency of multislice computed tomography (CT) has improved the ability to detect even subcentimeter lesions.

Patient selection

In general, good surgical candidates for pulmonary metastasectomy meet all of the following criteria:

  • No other known extrapulmonary metastases - If additional metastases are present, they should be considered amenable to surgical or some other form of therapy
  • Good surgical candidates from the standpoint of cardiopulmonary and other comorbid conditions
  • The location of the metastatic lesion is such that it can be completely resected with reasonable (depending on baseline pulmonary status) preservation of the remaining normal lung
  • The primary tumor site has been controlled or resected

Sometimes the resection is done to confirm the diagnosis (eg, to rule out a new primary cancer that might require a different approach to therapy).

A retrospective series from the National Cancer Institute spanning the period from 1979 to 2010 reported that given the dearth of effective systemic therapies, pulmonary metastasectomy may be the most beneficial treatment in patients who meet established selection criteria.[34]

Bronchoscopic Intervention

Local control by bronchoscopic intervention is reserved for symptomatic patients with tracheobronchial metastasis, provided that a reasonable life expectancy may be anticipated with successful resection. Options are as follows:

  • Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser resection of the endoluminal tumor
  • Electrocauterization
  • Argon plasma coagulation
  • Cryotherapy
  • Brachytherapy
  • Mechanical removal of the obstruction with rigid bronchoscopy
  • Endoluminal stent placement

Chemotherapy and Other Nonresective Treatments

Chemotherapy remains the treatment of choice for advanced cancer. Metastatic cancers known to respond favorably to chemotherapy include Hodgkin lymphoma, non-Hodgkin lymphoma, germ cell tumors, and thyroid cancer. A fair response to chemotherapy is expected for carcinomas of the breast, prostate, and ovary. Immunotherapy is an additional option for the treatment of metastatic malignant melanoma.

Several other therapies are currently being used as alternatives to surgical resection, including radiofrequency ablation (RFA),[35, 36, 37] cryoablation,[38] and conventional radiotherapy. However, most of these have limited availability, and most involve enrollment in a structured clinical trial.[39, 40, 41, 42]

These treatments are usually performed at experienced centers for patients who have lung malignancies (primary lung cancer or pulmonary metastases) and who are not candidates for surgery with the intent to resect. These therapies may also be used in conjunction with other treatments (ie, chemotherapy or radiotherapy) for better disease control. Repeat irradiation has been used for treatment of secondary lung tumors previously treated with radiotherapy.[43]

 

Questions & Answers

Overview

What are secondary lung tumors?

What are the pathologic mechanisms through which cancer spreads to the lungs?

What is the pathophysiology secondary lung tumors spread by direct extension?

What is the pathophysiology of metastatic spread secondary lung tumors?

What causes secondary lung tumors?

What are the signs and symptoms of secondary lung tumors?

What is the prognosis of secondary lung tumors?

Presentation

Which clinical history findings are characteristic of secondary lung tumors?

Which physical findings are characteristic of secondary lung tumors?

DDX

Which types of cancer are included in the differential diagnoses of secondary lung tumors?

Workup

How are secondary lung tumors diagnosed?

What is the role of lab testing in the workup of secondary lung tumors?

What is the role of cancer-specific tumor markers in the workup of secondary lung tumors?

What is the role of chest radiography in the workup of secondary lung tumors?

What are the advantages of CT scanning in the workup of secondary lung tumors?

What is the role of CT scanning in the workup of secondary lung tumors?

How are secondary lung tumors differentiated from benign lesions and primary cancers on CT scan?

What is the role of MRI in the workup of secondary lung cancers?

What is the role of PET scanning in the workup of secondary lung tumors?

What is the accuracy of PET scanning in detecting secondary lung tumors?

What is the role of PET-CT in the workup of secondary lung cancer?

What types of PET-CT scanners are used in the workup of secondary lung cancer?

What is the accuracy of PET scanning in detecting secondary lung tumors?

What is the role of PET-CT in the staging of secondary lung cancer?

What is the role of mediastinoscopy in the workup of secondary lung cancer?

What is the role of transthoracic needle aspiration (TTNA) biopsy in the workup of secondary lung cancer?

What is the role of transbronchial needle aspiration (TBNA) in the workup of secondary lung cancer?

What is the role of electromagnetic navigation bronchoscopy in the workup of secondary lung cancer?

What is the role of endobronchial ultrasonography (EBUS) in the workup of secondary lung cancer?

What is the role of esophagoscopy in the workup of secondary lung cancer?

What is the role of VATS in the workup of secondary lung cancer?

What is the role of immunohistochemistry in the workup of secondary lung tumors?

What is the role of gene expression in the workup of secondary lung tumors?

Treatment

How are secondary lung tumors treated?

When is surgery indicated in the treatment of secondary lung cancers?

What is the role of metastasectomy (wedge resection) in the treatment of secondary lung cancer?

What are the patient selection criteria for metastasectomy (wedge resection) to treat secondary lung tumors?

What types of bronchoscopic interventions are used in the treatment of secondary lung tumors?

What is the role of chemotherapy in the treatment of secondary lung tumors?

What are the alternatives to surgical resection for the treatment of secondary lung tumors?