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Secondary Lung Tumors

Author: Daniel S Schwartz, MD, FACS; Chief Editor: John Geibel, MD, DSc,
MSc, MA more...
Updated: Dec 08, 2014

Overview

Characteristics of Metastatic Primary Cancers

Pathophysiology
Etiology
Prognosis
History and Physical Examination
Differential Diagnosis
Laboratory Studies
Chest Radiography
CT Scanning
Magnetic Resonance Imaging
PET Scanning
Whole-Body PET Scanning (Oncologic PET-CT Scan)
Immunohistochemistry and Gene Expression
Mediastinoscopy
Aspiration and Biopsy
TBNA and PET scanning
Indications for Surgery
Chemotherapy and Other Treatments
Show All
References

Overview
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 wellcircumscribed, 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 based on 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 the continued systemic treatment with 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, 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 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 upon the underlying primary malignancy
and the selection criteria for surgery.

Diagnosis
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) scanning, or positron emission tomography (PET)/CT
scanning.
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 transcriptionpolymerase 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.

Characteristics of Metastatic Primary Cancers

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 mo).
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.

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, 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:

Melanoma
Thyroid cancer
Breast cancer
Colorectal cancer
Head and neck cancer
Renal cell cancer
Choriocarcinoma

Testicular cancer
Osteosarcoma
Ewing sarcoma
Wilms tumor
Rhabdomyosarcoma
Prostate cancer

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:

Pneumonia
Pulmonary thromboembolism
Tumor emboli syndrome
Pulmonary venoocclusive disease associated with certain cancers or
chemotherapies

Interstitial fibrosis secondary to chemotherapy or radiation

An infectious etiology
Mortality
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 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 diseasefree interval prior to the identification of metastatic disease (< 12 mo vs >12 mo).

History and Physical Examination

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.

Differential Diagnosis
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.

Laboratory Studies
The usual preoperative laboratory workup of any thoracic patient should include a
coagulation profile consisting of a platelet count, international normalized ratio,
and activated partial thromboplastin time. 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, colon cancer) at
an early stage.
This is reflected by the observation that lung metastases have been detected
using 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 1.6cm in diameter (which is far less
sensitive than CT scanning).
Overall, approximately 25% of the total lung volume is not readily accessible for
visual examination using plain posteroanterior chest radiography.
However, recognition of secondary pulmonary tumors has increased with
advances in this modality. Improvements in techniques, including the use of
Advanced Multiple Beam Equalization Radiography (AMBER) and a digital slotscan charge-coupled device (CCD) system, have increased the utility of this
simple and inexpensive staging modality.
LJ Kroft 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 scans as the criterion standard, failed to
confirm that these techniques had a significant advantage over standard chest
radiographs.[10]

CT Scanning

With the introduction of CT scanning in the 1970s, remarkable advances have

been made not only in clinicians ability to diagnose lung cancer but, more
importantly, in clinically staging it. CT scans can define the location, size, and
anatomic characteristics of a tumor far better and more precisely than chest
radiographs can[10] , and they are 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 todays CT-scan 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 scanning, the contribution of CT scanning to the staging of
patients with lung cancer is fluid.[11]
Using CT scanning, the identification of smaller lesions 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 scanning has also
resulted in an increased frequency of identification of nonmalignant lesions,
which must be distinguished from true malignancies.

Sensitivity and specificity

Conventional CT scanning 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
CT scanning further increases the odds of detecting pulmonary nodules.
Increased sensitivity comes at the cost of somewhat decreased specificity
compared with standard chest radiography (posteroanterior and lateral) and
conventional CT scanning. 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 (99m Tc)labeled somatostatin analogue depreotide single-photon
emission CT scanning is used for evaluation of pulmonary nodules and staging of
lung cancer, with reported sensitivity and specificity comparable to that of PET
scanning.
Indium-111 (111 In)labeled somatostatin analogue octreotide scanning is
recommended for localization of carcinoid tumors. Whole body iodine-131 ( 131 I)
scanning is recommended for the diagnosis of metastatic thyroid cancer.

Metastases versus benign lesions and primary cancers

In a patient with a known extrathoracic malignancy and a solitary pulmonary
nodule on CT scan, 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 scandetected 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 >3cm in diameter were malignant, compared with 20% of
nodules < 2cm), although autopsy data show that 57% of all metastases are 15mm 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 0.5cm in diameter increases
by 0.12cm in diameter, a nodule of 1cm increases by 0.26cm in diameter, a
nodule of 2cm increases by 0.52cm in diameter, a mass of 3cm in diameter
increases by 0.78cm 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
scanning with 3-dimensional (3-D) reconstruction of the nodule is a particularly
accurate method for assessing size changes.
Lymph nodes
Mediastinal nodes are considered positive on CT scans by size criteria; namely, if
the short axis is 1cm or greater. Nineteen percent of nodes from 0.5-1cm have
been reported positive for micrometastases. Seventy-five percent of lymph nodes
with cancer involvement are 1cm or greater in diameter.

High-resolution CT scanning 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
asymmetrical and is associated with fewer nodules and less distortion of
surrounding lung parenchyma.

Magnetic Resonance Imaging

MRI of pulmonary pathology offers little improvement over CT scanning 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. Its
use should be reserved for times when local tumor invasion of the mediastinum,
thoracic inlet, or paravertebral region is questioned on CT scanning. [12]

PET Scanning
PET scanning 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 imaging. It is a D-glucose labeled with a positronemitting18 F. 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 typically have a higher rate of glucose metabolism
than do normal cells. 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 scan.
PET scanning is currently used as a diagnostic and staging tool in cancer. In
particular, PET scanning 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 1cm in diameter. A standard
uptake value of greater than 3 is sensitive and specific for cancer.[15]
Limitations of PET scanning include an inability to detect brain metastases, falsenegative results in diabetic patients and in patients with malignant lung nodules
less than 1cm 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 when ordering this test.
Metabolic imaging of the lungs, such as with PET scanning, 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 scanning together were extremely useful in detecting lung
metastases larger than 1cm, as well as bone metastases. PET scanning had a
92.3% detection rate for secondary pulmonary nodules of 1cm or greater, but
only a 20% detection rate for lung metastases of less than 1cm. [17]
The investigators also found that chest CT scanning was significantly more
accurate than PET scanning in detecting lung metastases and that PET scanning
was significantly more accurate than bone scanning in detecting bone
metastases.

Whole-Body PET Scanning (Oncologic PET-CT Scan)

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

Types of PET-CT scanners

The terminology for PET-CT scanning software and hardware can be confusing.
The 3 primary modalities of PET-CT scanners are hybrid, fusion, and visually
correlated. The hybrid, or integrated, PET-CT scanner creates 2 images, with one
relying on CT scanning and the other on PET scanning. A computer then merges
the 2 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 3-D model of the CT-scan
study and a 3-D model of the PET-scan transmission 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 scanning, but it may not be as accurate as
integrated PET-CT scanning 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 scanning, 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 scan 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 scanning 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 scanning 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 scanning alone were lower,
reaching 68%, 66%, 88%, and 46%, respectively. With PET scanning alone, the
correct prediction rates were 46%, 70%, 96%, and 30%, respectively, and with
CT- and PET-scan visual correlation, the correct prediction rates were 72%, 68%,
96%, and 54%, respectively.

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.[23, 24, 25]
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.
These different aspects are currently being investigated in a diagnostic trial by a
collaborative group within the European Organization for Research and
Treatment for Cancer (EORTC CU003CR).

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-sided paratracheal, precarinal, and subcarinal lymphadenopathy. Left-sided
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 rate of 0.2%.

Aspiration and Biopsy

Transthoracic needle aspiration biopsy
Transthoracic needle aspiration biopsy (TNAB) 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%).[26] CT-guided TNAB was more sensitive than fluoroscopy-guided
TNAB, although 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 TNAB complementary procedures and
advocate their sequential use. TNAB 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, 016.6%). 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, brushneedle 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 2cm in diameter is 54%,
compared with 80% for those more than 3cm in diameter. For lesions located in

the lower lobe basilar segments or in the apical segments of the upper lobes,
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 and PET scanning

Combining transbronchial needle aspiration (TBNA) and PET scanning has been
shown to obviate the need for mediastinoscopy for mediastinal staging of nonsmall 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 scanning 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.

Navigation bronchoscopy with biopsy

This uses technology that allows the operator to approach a peripheral lung mass
using electromagnetic navigation 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.[27]

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 rate of serious adverse effects (< 1%), and
the procedure is touted as being highly accurate, with false negative rates
reported to be between 6% and 9%. EBUS-guided fine needle aspiration 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 (EUS) of
accessible lymph nodes is an alternative to transbronchial needle aspiration of

lymph nodes accessible from the esophagus. It appears to be complimentary to

EBUS.

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

Indications for Surgery

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 previously
considered a T4 tumor, as designated in the 1997 TNM classification scheme.
Currently, however, according to the International Association for the Study of
Lung Cancer, revised 7th edition TNM staging system, it is considered a T3
lesion.
According to the old classification, the presence of 2 malignant nodules of the
same histologic type in 2 different lobes on the ipsilateral side of the lung
indicated metastatic disease or stage IV lung cancer. According to the revised
staging system, however, this is indicative of potentially resectable T4 lesions. [28]
In both cases, surgical management that is more aggressive than 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
located in different lung lobes, because the approach is more aggressive if 2
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 of
the lesions proves benign.

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 preoperative lung function evaluation 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 selective 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 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 (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 a 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.[29] It can be counter-argued, however, that the efficiency of multislice CT
scanning 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 1979-2010
reported that because there is a dearth of effective systemic therapies,
pulmonary metastasectomy may be the most beneficial treatment in patients who
meet established selection criteria.[30]

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:

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 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.

Other therapies
Several other therapies are currently being used as alternatives to surgical
resection, including radiofrequency ablation,[31, 32] cryoablation,[33] and conventional
radiotherapy. However, most of these have limited availability and most involve
enrollment in a structured clinical trial.[34, 35, 36, 37]
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, radiotherapy) for
better disease control.
READ MORE ABOUT SECONDARY LUNG TUMORS ON MEDSCAPE
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Pulmonary metastases
Dr Henry Knipe and A.Prof Frank Gaillard et al.

Pulmonary metastases are common and the result of metastatic spread to the lungs from a variety
of tumours and can spread via blood or lymphatics.
This article is about with haematogenous pulmonary metastases with lymphangitis
carcinomatosis discussed separately.

Epidemiology
The epidemiology will match that of the underlying malignancy (see below), but as malignancies
increase in incidence with increasing age, so does the presence of pulmonary metastases.

Clinical presentation
Pulmonary metastases are usually asymptomatic, with constitutional symptoms relating to
disseminated metastatic disease and those attributable to the primary tumour
dominating 5. Haemoptysis and pneumothorax are sometimes the presenting symptom.

Pathology
Tumour cells reach the lungs via the pulmonary circulation, where they lodge in small distal vessels.
The most common primaries to result in pulmonary metastases include 1,3:

breast carcinoma

colorectal carcinoma

renal cell carcinoma

uterine leiomyosarcoma

head and neck squamous cell carcinoma

Alternatively, primaries which most frequently metastasise to lungs (although in themselves much less
common tumours) include 1,3:

choriocarcinoma

Ewing sarcoma

malignant melanoma

osteosarcoma

testicular tumours

thyroid carcinoma

Primaries that metastasize as endobronchial deposits can include:

colorectal carcinoma

renal cell carcinoma

lung cancer

lymphoma

Radiographic features
Pulmonary metastases typically appear as peripheral, rounded nodules of variable size, scattered
throughout both lungs 1. Atypical features include consolidation, cavitation, calcification, haemorrhage
and secondary pneumothorax.

Plain radiograph
Plain films are insensitive, although frequently able to make the diagnosis, as often pulmonary
metastases are large and numerous.

CT
CT is excellent at visualising pulmonary nodules. Typically metastases appear of soft tissue
attenuation, well circumscribed rounded lesions, more often in the periphery of the lung. They are
usually of variable size, a feature which is of some use in distinguishing them from a granuloma 3.
A prominent pulmonary vessel has frequently been noted heading into a metastasis. This has been
termed the feeding vessel sign 4. It is unclear whether this is a true finding or the result of older
scanners with thicker slices resulting in volume averaging 4. However, a number of atypical features
are commonly encountered.
Some tumours have a predilection for innumerable small metastases (miliary pattern):

malignant melanoma

osteosarcoma

renal cell carcinoma

thyroid carcinoma

trophoblastic disease 3

Conversely, a pulmonary metastasis may be single. This is most frequently seen in colorectal
carcinoma. Other primaries which often present with solitary metastases include 3:

malignant melanoma

skeletal sarcoma

testicular carcinoma

adenocarcinomas in general

Adenocarcinoma metastases may rather than displace or destroy adjacent lung parenchyma, cells
grow in a lepidic fashion (spread along aleveolar walls) resulting in pneumonia-like consolidation. Air
bronchograms may also be visible 1.
Cavitation is present in ~4% of cases 1. The most common primary is squamous cell carcinoma, most
often from the head and neck or from the lung. Other primaries include adenocarcinomas, and
sarcomas 1,3.
Calcification, although uncommon and more frequently a feature of benign aetiology (e.g. granuloma
or hamartoma) is also seen with metastases, particularly those from papillary thyroid carcinoma and
adenocarcinomas. Treated metastases, osteosarcomas and chondrosarcomas may also contain
calcific densities 1.
A halo of ground-glass opacity representing haemorrhage can be seen, particularly
surrounding haemorrhagic pulmonary metastases, such as choriocarcinoma andangiosarcoma 1.

MRI
Although not used routinely, MRI may be as sensitive in the detection of pulmonary metastases as
CT 2,4.

Treatment and prognosis

In general presence of pulmonary metastases is an ominous finding, indicating poor prognosis. The
specific prognosis will however depend on the primary tumour.

Complications
Tumours with prominent necrosis located near a pleural surface may result in a
pneumothorax. Osteosarcoma is classically described as the pulmonary metastasis that results in
pneumothorax. Another cause of pneumothoraces include cystic or cavitatory pulmonary metastases.

Differential diagnosis
The differential depends on the number of nodules/masses and their imaging characteristics.

differential of multiple pulmonary nodules

differential of a single pulmonary nodule

differential of miliary pulmonary nodules

differential of a cavitating lung mass

differential of a pulmonary mass with calcification

differential of a pulmonary mass with surrounding ground-glass halo

Related articles
Lung cancer

lung cancer: overview

o

non small-cell lung cancer[+]

pulmonary neuroendocrine tumours[+]

preinvasive lesions[+]

benign neoplasms[+]

pulmonary metastases

cannonball metastases

cavitatory pulmonary metastases

cystic pulmonary metastases

lung cancer screening[+]

lung cancer staging[+]

References