Continuing Education Activity

The lung is one of the most common sites of cancer metastasis. This activity will provide an overview of the common cancers that metastasize to the lung, the diagnostic work-up, and currently available treatment options. It will also review the molecular basis of metastasis and the critical role of genetics, epigenetics, cytokines, and chemokines involved in the pathophysiology of metastasis. The importance of an interprofessional team to diagnosis and management will be reviewed.

Objectives:

• Identify the common tumors metastasizing to the lungs and their radiologic pattern.
• Outline the underlying genetic and molecular biological pathways leading to metastasis of cancers to the lung.
• Review the diagnostic workup for suspected lung metastasis in patients.
• Describe some interprofessional team strategies for improving care coordination and improve outcomes in lung metastasis.

Introduction

Metastasis is a term used to describe the spread of tumor cells from primary sites to surrounding structures and distant sites. It is considered a significant cause of morbidity and mortality. Distant metastasis is an indicative marker of the aggressive nature of the primary tumor.

Metastasis to the lung is a complex multistep process. Metastatic tumor cells go through stages of detachment from the primary tumor sites, invasion into vessels (capillary, lymphatics), extravasation into the appropriate secondary site, the establishment of a microenvironment supporting its nourishment and blood supply. Common cancers that metastasize to lung parenchyma include breast, lung, colorectal cancer, uterine leiomyosarcoma, and head/neck squamous cell carcinomas. Cancers that spread to the endobronchial tree of lungs include colorectal, renal, lung cancer, and lymphomas. Other tumors that can metastasize to the lungs include osteosarcoma, testicular tumors. Other rare cancers described in the literature that metastasize to the lung include adrenal, thyroid, choriocarcinoma, hypernephroma. Some tumors cannot be identified and classify as cancer of unknown primary (CUP). Around 90% of CUP are adenocarcinomas (90%), with squamous cell carcinomas and undifferentiated carcinomas reportedly less frequent.[1][2]

Etiology

Histologic, genetic, and pathologic features of tumors guide them to metastasize to specific sites.

Tumors spread to the lungs either by hematogenous or lymphatic route or by direct invasion.

1. Hematogenous spread: seen in tumors with venous drainage into lungs, e.g., head and neck, thyroid, adrenals, kidneys, testes, melanoma, and osteosarcoma.
2. Lymphatic spread: occurred in two ways: either antegrade lymphatic invasion through the diaphragm and/or pleural surfaces or by retrograde lymphatic spread from hilar nodal metastases. Examples include lung, stomach, breast, pancreas, uterus, rectum, and prostate cancer.
3. Direct spread to pleura: occurs due to hematogenous dissemination with extension to the pleura, with lymphatic spread, or from established hepatic metastases. Examples include cancers of the lung, breast, pancreas, and stomach.[2]

Multiple lung nodules in the setting of the primary tumor are highly suspicious of metastatic lung ca, however solitary nodules in the presence of primary tumors can be metastatic (melanoma, sarcoma), or it can primary lung tumor.

Epidemiology

The lung is the second most frequent site of metastatic focus. It is estimated that 20 to 54% of malignant tumors developing elsewhere in our body would have pulmonary metastasis.[3][2]  

Patients with metastasis to the lung have clinical prognosis and treatment options very different from their primary tumor of origin.

Distant metastasis plays an important role in the staging of the tumor. e.g., distant metastasis of breast cancer decreases the 5-year survival from 96% to 21%. In colorectal cancer, patients who present with metastasis to the lung or liver have a 5-year survival of less than 10% compared with 91% of those without distant metastasis.  

About 1500 people die every day from metastatic cancers, indicating limitations of the modern-day treatment options once the disease is widespread.[1]

A study was conducted on 228 patients with lung nodules. The study revealed the median age of the group was 61.8 yrs. About 53.5% were male, 46.5 % female. The primary tumor site  in these patients was as follows:

• Colorectal in 25.8%,
• Head and neck 19.4%
• Urologic (kidney, ureter, prostate, testes) 14.7%
• Gastrointestinal non-colorectal cancer 10.9%
• Breast cancer 10.5%
• Melanoma 6.5%
• Gynecologic cancer (ovarian, endometrial, cervical) 6.1%
• Other primary sites (sarcoma, thyroid, squamous cell) 6.1%
• Concomitant extra pulmonary nodules were present in 25.9% of cases.

A single nodule was present in 49.1 and multiple in 50.9 cases. Size of pulmonary nodules range from 20 to 30 mm ( 50%), 10 to 20 mm (28.5%), < 10 mm (21.5%). Cavitary or necrotic nodules were present in 88.5% of cases and absent in 11.5 % of cases. Patients previously received thoracic radiotherapy in 8.3% of cases. Regarding smoking history, 61% of patients were current or former smokers, 30.3% were never smokers, and data was not available for 8.7% of cases. After the biopsy, metastatic disease was present in 146 patients (64%), 60 patients (26.3%) were diagnosed with a second primary lung tumor, and 22patients (9.6%) had no cancer on biopsy. The presence of a malignant lesion on biopsy was much higher with concomitant multiple lung lesions. The study concluded that multiple pulmonary nodules (> 5 mm) and cavitation were the two characteristics associated with the highest chances of metastatic disease. Pulmonary nodules should not be assumed to be metastases without performing a biopsy.[4]

There has been a case reported where a single patient had simultaneous lung adenocarcinoma and metastatic breast cancer nodules in a single lung.[5]

Pathophysiology

Many theories have been proposed regarding the origin of metastatic cells involve in the spread of the tumor.

1. Epithelial to mesenchyme transition (EMT): Epithelial stem cells transform into mesenchymal cells by the step-wise accumulation of gene mutations. These mesenchymal cells form metastatic neoplastic cells. They lack cell-cell adhesion, are dysmorphic in shape, and have the capacity to spread to distant organs.
2. Stem cell origin of metastatic tumors: Tissue stem cells are considered to be the origin of metastatic cancers due to similarities in gene expression and biological characteristics. This theory is supported by the fact that both cancer cells and stem cells have high telomerase activity that links to the use of high anaerobic energy (fermentation) for metabolism. Both cells survive and grow on the same anaerobic energy source.
3. Macrophage facilitation of metastasis: Tumor-associated macrophages (TAM), especially those in the stroma, facilitate tumor development, progression, and the eventual seeding of metastasis. Researchers do not consider them neoplastic. However, many human metastatic tumors also contain neoplastic cells with macrophage properties. It is not possible to differentiate neoplastic macrophages from non-neoplastic ones.
4. Myeloid cell origin of metastasis: Metastatic cancer cells arise directly from myeloid origin cells or hybrid cells formed by fusion between macrophages and non-metastatic stem cells. Myeloid cells have mesenchymal properties promoting metastasis and are the precursors of macrophages that promote the metastatic cascade. An alternative explanation of this theory is that macrophages fuse with epithelial cells within the inflamed microenvironment, thus manifesting properties of both the epithelial cell and the macrophage in the fusion hybrids. These fusion hybrids then form the metastatic cells possessing epithelial and macrophage properties.[6]

Metastatic spread is also under the control of a combined play of genetic or epigenetic factors.

Smoking exposure correlates to the activation of the ubiquitin- chemokine receptor type 4 (CXCR4) pathway, high tissue levels of E-selectin, activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF_B) signaling in pneumocytes, increased chemokine ligand 2 (CCL2) expression and macrophage infiltration in the lung microenvironment. This chemokine secretion by alveolar cells recruit neutrophils, which in turn synthesize arachidonate 5-lipoxygenase (ALOX5)-dependent leukotriene. Leukotriene promotes survival and proliferation of leukotriene B4-expressing metastatic clones. Neutrophils also secrete cathepsin G and elastases, which further facilitate metastatic growth.

The fate of the cells that reach the distant focus will be either ended up in apoptosis, survival, or dormancy. Distant metastatic cells dormancy period varies, e.g., short ( few weeks) in lung cancer, long ( years/decades) in ER + breast ca, prostate cancer.

Also, recent discoveries show that metastatic focus gets prepared before the arrival of the metastatic cells themselves.

Before the actual arrival of metastatic cells, a microenvironment gets created by interaction among:

• Cell-intrinsic determinants, e.g., chemokines, cytokines
• Adhesion and extracellular matrix molecules, for example, tenascin and periostin.
• Tumor-derived exosomes

Intrinsic Cell Determinants 

Metastatic cells utilize cell-autonomous traits that facilitate homing and survival by altering the following genes:

1. Gene of Rous sarcoma virus (SRC) tyrosine kinase signaling
2. P38 and extracellular signal-regulated kinase-1 (ERK) mitogen-activated protein kinase (MAP) kinase signaling pathways

By those alterations, metastatic acquire a stem-cell-like genetic profile.

 Various stromal cells, including fibroblasts, neutrophils, and vascular endothelial growth factor receptor 1 (VEGFR1)-positive bone marrow-derived hematopoietic progenitor cells play a crucial role in niche preparation.

It is worth noting that the metastatic niche can be stimulating or suppressive.

1. In the prostate cancer metastasis model, mitogen-activated protein kinases 7 (MKK7) suppress the formation of lung metastases by inhibiting the ability of disseminated cells to colonize the distant tissue.
2. Bone morphogenetic proteins (BMPs) and growth arrest-specific 6 (GAS6) proteins produced by osteoblasts can directly inhibit disseminated tumor cell proliferation. Single cells enter arrest immediately upon infiltrating the lung and are therefore unable to form micrometastatic lesions.

Adhesion and extracellular matrix molecules: To establish metastatic mass, circulating neoplastic cells need to adhere to endothelial walls and extravasate to reach the lung parenchyma. 

1. VCAM 1 (vascular cell adhesion molecule 1) has been reported in secondary lung masses from breast cancer. It expresses on endothelial cells. Upon activation, it initiates trans-endothelial migration by binding specific integrins, which in turn induce the activation of GTPase Ras-related c3 botulinum toxin substrate. Activation of GTPases causes modification of the cytoskeleton network and facilitates cell migration.
2. SSeCKS (scaffold protein src-suppressed C-kinase substrate complex) dysregulation occurs in lung metastases from melanoma. It is known to control metastasis-associated protein kinase C (PKC) and SRC (Gene of Rous sarcoma virus) signaling through direct scaffolding activity.
3. Colony-stimulating factor 1 (CSF1) acts as the mediator of lung metastases. It recruits macrophages, which, in turn, secrete epidermal growth factor, followed by CSF1 secretion by tumor cells and further recruitment of macrophages. The presence of macrophages indicates highly invasive potential, which enhances the formation of neoplastic lung colonies. 
4. Successful metastasis formation requires early remodeling of the lung ECM in the metastatic niche. Tumor-related tenascin C  is a protein that is deemed essential in the early phases of metastatic onset. There is a direct correlation between the expression of the extracellular matrix glycoprotein tenascin C and breast cancer metastasis to the lung. Tenascin C enhances the Wingless-related integration site (WNT) and NOTCH signaling pathway, which plays a critical role in improving the viability of cancer cells.
5. Periostin is an ECM protein involved in metastatic lung development. Mice without periostin gene presence develop a reduced number of lung metastasis in the setting of mammary tumors. 

Tumor-derived Exosomes

Exosomes are small membrane-bound vesicles of endocytic origin that can transport molecules, including proteins, DNA, RNA, and non-coding RNA, from one cell to another. They can disseminate via the bloodstream and can induce changes in distant sites to establish a favorable environment for the cancer cells.  

In the cancer setting, tumor-derived exosomes have demonstrated being taken up by organ-specific cells to prepare the pre-metastatic niche. e.g., mice injected when with tumor cells that have a predilection to metastasize to the lung interact with the lung epithelial lining cells.  

Lung-tropic exosomes expressing the integrin preferentially interact with S100A4-positive fibroblasts and surfactant protein-positive pneumocytes. RNAs in tumor exosomes can activate toll-like receptor 3 in alveolar type II cells. It induces chemokine secretion and neutrophil recruitment in the lung. These steps are critical for initiating the formation of a metastatic niche in the lung.

Exosomes coded proteins help to establish a favorable environment at distant sites.

These proteins include tenascin, bone morphogenic protein inhibitor. Tenascin C increases the concentration of growth factors such as EGF, vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), which promotes the growth of metastatic masses.

Bone morphogenic protein inhibitor (COCO) regulates the cycle of tumor dormancy and activity in the lungs and promotes metastasis of breast cancer cells to the lungs but not to the bone or brain.

Colorectal cancer cells that metastasize have specific markers CD110 and CDCP1, which adhere to the epithelium of the liver and lung, encouraging organ-specific metastasis. 

Genetic Factors Predisposing Cancers to Metastasis

Analysis of metastatic adenocarcinoma nodules of different origin (lung, breast, prostate, colorectal, uterus, ovary) and comparison with the expression profiles of 64 primary adenocarcinomas revealed the same spectrum, though the primaries were different and researchers obtained samples from different individuals. This comparison allowed the identification of an expression pattern of 128 genes that best differentiate primary and metastatic adenocarcinomas.

Similarly, the gene expression profile analysis of a subset of primary breast tumors generated a unique 14-gene signature expression(WDR6, CDYL, ATP6V0A4, CHAD, IDUA, MYL5, PREP, RTN4IP1, BTG2, TPRG1, ABHD14A, KIF18A, S100PBP, and BEND3). With the help of this, clinicians can predict the risk of the development of visceral organ metastases.

Inhibitor of cell differentiation 1 (ID1), matrix metalloproteinase 1 (MMP1), chemokine CXC motif ligand 1 (CXCL1), prostaglandin-endoperoxide synthase (PTGS2), vascular cell adhesion molecule-1 (VCAM1), and epiregulin (EREG) are the genes that promote lung metastasis in animal models carrying breast carcinoma. ID1 promotes the formation of lung metastases by itself in animal models and expresses significantly in samples from breast cancer patients with lung metastases. Its activation promotes breast cancer dissemination by modulating S100A9 expression.

Analysis of human cancer samples has shown that the comparison of lung and non-lung metastases from breast cancer identified 21 differentially expressed genes, which mainly encode adhesion molecules, resulting in the cell to cell interactions and thus facilitating lung colonization. Among them are integrins (ITGB8), cadherins (CDH3), desmosomal proteins (DSC2), and focal adhesion molecules (FERMT1).

Epithelial to Mesenchyme Transition 

Concerning the epithelial-to-mesenchymal transition (EMT), a step required for metastatic dissemination, the miR-200 family has been reported as a critical mediator in regulating E-cadherin expression. Many miRNAs control the angiogenic process. The mir-143-3p expression decreases in a metastatic osteosarcoma cell line (143B) and primary osteosarcoma tissues with lung metastasis. Increased expression of miR-27a,  decreased miR-95-3p, miR-195 expression, and miR-133 dysfunction are associated with cancers that develop lung metastasis.   

In colorectal cancer, the overexpression of miR-885-5p resulted in significantly induced cell migration, invasion, and stress fiber formation in vitro. It was associated with the development of liver and lung metastases in in-vivo models.

Mechanical Interaction Between the Metastatic Cell and Distant Site 

Mechanical interaction between tumor mass and surrounding parenchymal structures also play a role in metastasis. Per one study, tumors should be at least 1.5 times stiffer than their surrounding healthy tissue to exert a sufficient compressive force to overcome confinement by the host tissue. Such compression forces progressively shrink the surrounding interstitial space hence concentrating tumor-promoting growth factors and cytokines. These stresses may play a role in tumor angiogenesis, either through direct upregulation of VEGF secretion or indirectly due to induced tissue hypoxia.

 The ECM near a tumor is typically rather dense due to increased matrix deposition, collagen crosslinking through enzymes such as lysyl oxidase, and an intense fibrotic response known as desmoplasia. It promotes cell invasion and migration by elevated tissue stiffness. This stiffening routinely gets exploited clinically to detect tumors through physical palpation and by commonly used imaging techniques.

The occurrence of ECM stiffening around metastatic lesions at similar levels as that of the primary tumor is a feature in pancreatic cancer. ECM stiffening activates mechano-transduction signaling pathways, which drive force-dependent integrin clustering and subsequent increased focal adhesion assembly and disruption of adherens junctions by cytoskeletal contractility.[2]

Circulating metastatic cells also can withstand the metabolic challenges in the future site of colonization. In lung metastasis, tumor cells upregulate PPAR gamma coactivator-1-alpha (PGC-1alpha ) expression. PGC-1 alpha stimulates the expression of antioxidant genes, which can help lung metastases cope with increased oxidative and chemical toxicity. Another antioxidant mechanism found to play a role in lung metastasis is the upregulation of peroxiredoxins. Peroxiredoxins are small antioxidant proteins that shuttle electrons to reduce hydrogen peroxide, hence decreasing reactive oxygen species.[7]

Besides that, the pericyte of lung epithelial cells plays a role in anchoring metastatic cells. A study in which researchers deleted the pericyte gene KCL4 in mice resulted in fewer premetastatic niches and less lung metastasis.

Histopathology

Once metastasis is found within the lung, the next step is to discover whether they arise from the lung or a distant focus. Immunohistochemical stains play a pivotal role in the identification of metastatic focus origin.

The identification of metastasis to the lung uses immunohistochemical stains into different cell lineages. i.e., epithelial, mesenchymal, lymphoid, melanocytic.

In the case of epithelial-derived lesions, the expression of thyroid transcription factor 1 (TTF-1) is a highly specific marker for primary lung adenocarcinomas. It requires inclusion in diagnosis between primary and metastatic adenocarcinomas of the lung. TTF-1 is a tissue-specific transcription factor that plays an important role in the early embryonic differentiation and morphogenesis of both lung and thyroid. In adults, it almost exclusively expresses in thyroid and pulmonary epithelial cells. It is highly specific in differentiating lung epithelial cancer (TTF-1 positive) pulmonary metastases of extra-thoracic origin. It bears mentioning that some adenocarcinoma markers may also express in a small minority of lung metastases of distant primary epithelial tumors such as breast, ovarian, and hepatocellular cancers.

To differentiate neuroendocrine lung tumors, INSM1 (Insulinoma-associated protein 1) is a  transcriptional factor. It is inactivated by the HES1 (Hairy and Enhanced of Split-1) transcription factor. It promotes the expression of three neuroendocrine molecules: chromogranin A (CHGA), synaptophysin (SYP), and neural cell adhesion molecule 1 (NCAM1) via activation of transcription factors. INSM1 is emerging as a novel, sensitive, and specific IHC marker that may serve as a first-line marker of neuroendocrine differentiation.[2]

History and Physical

Patients with lung metastasis either have a known primary tumor or present the first time with the lung metastasis.

They can be symptomatic or asymptomatic. Lung metastasis can present in the form of solitary or multiple metastases.

Symptoms

The patient can be asymptomatic and incidentally found to have lung nodules.

Systemic symptoms: fatigue, nausea, anorexia, weight loss

Localized symptoms:

• Pleurisy/pleural effusion
• Cough (productive and non-productive)
• Dyspnea
• Hemoptysis
• Scalp metastasis
• Electrolyte disturbances
• Pancoast tumor
• Superior vena cava syndrome

Common symptoms associated with metastatic cancers in general, reported in the survey are vomiting, 40 cases (25%), low back pain, 38 cases (24%), loss of appetite, 32 cases (20%), and shoulder pain, 27 (17%).[8]

Physical

Lung exam: normal or may indicate monophasic wheezing if any bronchogenic mass is present, crackles if alveoli filled with fluid or post obstructive pneumonia, decrease breath sounds if pleural effusion or atelectasis.

• Digital clubbing
• Weight loss
• Lymphadenopathy
• Pancoast tumor signs (including Horner syndrome)
• Superior vena cava syndrome signs[9]

Evaluation

Abnormal lab suggesting metastatic disease includes anemia, hypercalcemia, and electrolyte disturbances (SIADH).

A chest X-ray is initial imaging usually performed in both symptomatic patients and patients with known primary tumor. It is cost-effective and readily available. The downside is that small metastasis or miliary distribution is not visible. In one study, high kilovolts radiation helps detect pulmonary nodules up to 5 to 10 mm on a chest X-ray.

Computed tomography (CT) of the chest is the next option, with helical or multi planer projection or maximum intensity projection to increase sensitivity. Spiral CT is more sensitive due to a higher rate of detection of metastasis than other imaging techniques. Up to 72% to 97% nodules and as little as 3 mm nodules are detectable on 5 to 10 mm slices. The sensitivity of CT scan decreases due to high false-negative attributed to unequal respiratory cycles.[10]

Positron emission tomography (PET) with fluorodeoxyglucose (FDG) is used to detect metastasis elsewhere in the body. PET-CT is used for the precise location of metastasis superimpose on a CT scan.

Magnetic resonance imaging (MRI), on the other hand, has not improved the diagnosis of lung metastases compared with conventional CT. It is specifically indicated for showing tumor invasion of the great vessels, chambers of the heart, chest wall, and spinal column and can help rule out synchronous liver metastases.

Flexibltracheobronchoscopy with endobronchial ultrasound (EBUS) is a standard component of the preoperative diagnostic workup. It allows the evaluation of the mucosa and confirmation of the histology of centrally located metastases. In combination with endobronchial ultrasound, it helps in determining the status of the peribronchial and mediastinal lymph nodes.

CT guided biopsy for peripherally located lesions or lesions that are near large vessels.

Mediastinoscopy

For peripheral foci up to 3 cm in size, video-assisted thoracic surgery (VATS) has become established for use as a diagnostic procedure with a low complication rate.

After obtaining a tissue biopsy, genetic, cytologic, immunohistologic testing follows to identify the source of the metastasis.

Because lung metastasis gets detected on imaging studies, it is essential to recognize the pattern suggesting a particular route of spread.

Imaging

Specific patterns associated with different tumors on CT chest include Diffuse miliary seeding (medullary carcinoma of the thyroid), large singular metastases (choriocarcinoma, melanoma, and hypernephroma), calcification of metastases (osteosarcoma, adenocarcinoma, and secondary to chemo- and radiation therapy), and cavitation of pulmonary metastases (squamous cell carcinoma of the head and neck and from the genitourinary tract in women).

Most of the hematogenous metastasis appears to happen from the distal pulmonary artery nidus of metastatic tumor cells, resulting in most of the metastatic focus on basal and peripheral segments of the lungs.[11]

Chest x-ray patterns recognized with lung metastasis via lymphatic spread include reticular or reticulonodular interstitial markings, thickening of the interlobular septa (Kerley B lines), hilar adenopathy, and pleural disease. High-resolution CT is sensitive to detecting patterns such as thickened core structures in the central portions of the secondary pulmonary lobules.[11]

On plain films and CT scans, pleural metastases may appear as nodules or plaque-like formations. Malignant pleural effusions, seen in around 42% of cases, most commonly arise from primary tumors of the lungs, the breast, and the ovaries, and lymphoma.

Treatment / Management

Different treatment options are available based on the underlying tumor pathology, immunohistopathology. No prospective comparative trials yet exist that might provide evidence for prolonging survival by surgery or chemotherapy, or radiation. There are no randomized, controlled trials yielding evidence that would help decide whether to treat pulmonary metastases with surgery, radiotherapy, or chemotherapy (or some combination of these).

Chemotherapy

Chemotherapy is usually not curative for pulmonary metastases, except few tumors. e.g., first-line cisplatin-based therapy for germ cell testicular tumors produces a high long-term cure rate. 

It plays a significant role in the treatment of osteogenic sarcomas. Neoadjuvant administration of chemotherapeutic agents can reduce tumor burden and help to control systemic metastases. Neoadjuvant agents, e.g., methotrexate, cisplatin, doxorubicin, and ifosfamide, decrease the preoperative tumor burden. About one-third of all lung nodules disappeared after preoperative chemotherapy. Patients also received treatment with postoperative adjuvant chemotherapy. 2-year disease-free survival after chemotherapy and surgery was 56%

Similar results occurred in patients treated with chemo and surgery in osteosarcoma with pulmonary metastasis compared to chemotherapy alone. In another study, patients received treatment with neoadjuvant ifosfamide, surgical resection. After surgery, the postoperative adjuvant was with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin. Patients with fewer than eight metastatic deposits confined to the lung had a 5-year disease-free survival rate of 66.7%.

Cure rates of non-metastatic high-grade osteosarcomas have increased to 60 to 70% by the addition of adjuvant and neoadjuvant multiagent chemotherapy. In the treatment of metastatic osteosarcoma patients, surgical removal of all metastatic foci is essential. In re-recurrences, repeated thoracotomies and metastasectomies for resectable lesions are necessary. Some studies found a positive survival effect of second-line chemotherapy. Radiotherapy may be a consideration in patients without second complete remission.

Chemotherapy failure is usually due to drug resistance and toxicity. However, by isolated lung perfusion, one can deliver high-dose chemotherapy to the lung metastasis only, thereby avoiding systemic toxicity. Studies in the rodent model found that high-dose melphalan delivered via isolated lung perfusion eradicated metastatic pulmonary sarcoma with acceptable toxicity. 

Immunotherapy

Tumors such as malignant cutaneous melanoma and renal cell carcinoma are highly immunogenic and known to respond to immunotherapy.

A multivalent vaccine against melanoma is now available. Research has demonstrated that surgical resection and postoperative vaccine immunotherapy used for melanoma had significantly better survival than did patients treated non-surgically. Vaccine therapy offers the advantages of long-term efficacy and low toxicity when compared with traditional cytotoxic chemotherapy. Underway is a phase III multicenter trial of the vaccine as adjuvant therapy following surgical resection of metastatic melanoma.

Naturally occurring cytokines such as tumor necrosis factor (TNF)-alpha, interferon (IFN)-γ, and interleukin (IL)-2 can produce excellent response rates to a variety of solid organ tumors but have high systemic toxicity that requires reducing the dose or stopping treatment. 

The National Cancer Institute (NCI) performed a feasibility study of cytokine therapy delivered by isolated lung perfusion with moderate hyperthermia. Fifteen patients with nonresectable pulmonary metastases from various malignancies had treatment with single-lung isolation perfusion of TNF-alpha and IFN-gamma, a synergistic combination. Only 20% of patients had a temporary decrease in perfused nodules.

Inhaled IL-2 on pulmonary metastases from renal cell carcinoma with or without low-dose systemic IL-2 resulted in 70% cases, regression or stabilization of disease, with a median response duration of 8 months. Only moderate dose-dependent local toxicity, such as a dose-dependent cough, but there were no reports of significant systemic toxicity.

Radiation

Radiation is thought to increase the expression of major histocompatibility complex (MHC) class I and II molecules on tumor cells and tumor antigenic markers, enabling the immune system to increase antitumor activity and T-cell-mediated tumor immunity.

Radiation therapy does not significantly increase survival rates in patients with pulmonary metastasis, except in patients with lymphomas. Unfortunately, the dose required for effective tumor control exceeds the tolerance of normal lung tissue. The present convention is to deliver a fraction of 200 to 300 cGy daily. The current challenge is increasing the radiosensitivity of pulmonary metastases relative to the surrounding normal lung tissue to avoid damage to healthy lung tissue while treating pulmonary metastasis with adequate radiation dose. Intratumoral placement of radioisotopes or brachytherapy has shown some benefits in patients unsuitable for other therapeutic approaches. 

The role of radiation is mostly palliative in lung metastasis. It can be beneficial to control pain from metastases that invade the chest wall or mediastinum. When combined with other therapies, external beam radiation to the lung can improve outcomes and decrease relapses. About a third of patients with metastatic Ewing sarcoma present with lung and/or pleural nodules as their only metastatic site. The addition of whole-lung radiation of 1400 to 1800 cGy to conventional chemotherapy in patients with pulmonary metastases from Ewing's sarcoma resulted in more prolonged survival and a reduced rate of pulmonary recurrence when compared with patients receiving only chemotherapy.

A murine renal cell carcinoma model was used to demonstrate a synergistic relationship between radiation therapy and immunotherapeutic agents.

Patients with papillary thyroid carcinoma with pulmonary metastases have a poor prognosis. Radioactive iodine is the only non-surgical therapy effective in reducing metastatic tumor burden and improving survival.

Differential Diagnosis

• Primary lung tumor
• Pneumonia
• Fungal infection/mycetoma
• Miliary tuberculosis
• Hamartoma
• Adenomatous hyperplasia
• Amyloidosis
• Solitary fibrous tumor
• Melanoma (a new primary tumor)
• Anthracosis
• Scar tissue[4]

Surgical Oncology

If metastases are restricted to the lungs, surgery within the overall oncological treatment is justified. However, since a prediction of survival is not possible without an operation, and the utility of surgery remains untested in a prospective randomized study, the decision for or against metastasectomy must be made on a case-by-case basis.

The criteria for selecting patients to undergo surgical resection of lung metastases are:

• Technical resectability
• Tolerable general and functional surgical risk
• Control of the primary tumor process
• Exclusion of any further extrathoracic metastasis.

Favorable prognostic factors after surgical treatment of pulmonary metastasis depend on the following factors:

• A long disease-free interval between the treatment of the primary tumor and the discovery of pulmonary metastases
• Absence of thoracic lymph node metastases
• A small number of pulmonary metastases

The standard procedure is circumscribed atypical (lung tissue-sparing) resection; more rarely, anatomic resection such as pulmonary segmentectomy or lobectomy is necessary. If anatomical resection not possible due to multiple metastases, centrally located metastasis using neodymium YAG laser should be attempted, or a pneumonectomy is an option. 

The role of lung metastasectomy by VATS as a curative procedure to achieve local radical resection comparable with that obtained by thoracotomy has yet to be studied. Extend of resection and lymph node dissection has not been defined in any of the studies.

In one study, malignant pulmonary foci that had not been detected by preoperative CT were detected in 20% of patients by intraoperative palpation. So far, thoracoscopic procedures have not been generally recommended for curative intent since the lung tissues are not accessible to palpation, similar to an open procedure.

5-year survival rates after pulmonary metastasectomy, depending on the primary tumor, are 35.5% to 47% for renal cell carcinoma, 39.1% to 67.8% for colorectal cancer, 29% to 52% for soft-tissue sarcoma, 38% to 49.7% for osteosarcoma, and 79% to 94% for non-seminomatous germ-cell tumors. For the latter two types of tumors, chemotherapy is the most beneficial treatment for long-term survival.

If there are widespread diffuse pulmonary metastases, or if the lesions are technically or functionally inoperable, local interventions such as surgery and radiotherapy are at best palliative.  

Patients with complete resection (R0) of a solitary disease focus and a disease-free interval of more than three years after surgery to treat the primary tumor showed the most favorable prognosis. Although this study contained no control group of non-operated patients, the significantly more favorable 5-year survival after R0 resection (36%) compared to incomplete resection (13%) indicates the chances of success of metastasectomy. Operative mortality reported was 1%.

Solitary recurrent metastasis in the lung requires investigation for whether repeat resection is indicated. A longer interval of time between the first metastasectomy and the appearance of recurring metastases appears to be prognostically more favorable. Primary tumors patients who undergo one recurrence metastasectomy achieved a median survival time of more than 60 months; with two recurrence metastasectomies, median survival was 34.7 months, and with three or more, it was 45.6 months. Nonsurgical candidates had a  median survival of 8 months.

Special Tumors and Considerations

Colorectal cancer:  1% to 2% of patients undergo pulmonary metastasectomy. Stage IV tumors demonstrate survival of 24 months; after metastasectomy, 5-year survival of 68% is possible. In the presence of synchronous liver metastasis, 5-year survival is 42% after lung and liver metastasectomy.

Renal cell cancer (RCC): Chemotherapy plays a pivotal role in RCC, but surgery can be performed with curative intents, especially if there is no thoracic lymph node involvement. Thoracic lymph nodes are present in 30% to 45% cases, decreasing survival after surgery between 64 and 92 to 26 to 29 months.

Breast cancer: The median survival time for patients with lung metastasis was 21 months, and 15.5% of the patients were alive for more than three years. The tumor subtype distribution was 45.3% HR−/HER2−, 12.2% HR+/HER2+, 7.8% HR−/HER2+, and 15.0% triple-negative subtype. Compared with patients without lung metastasis, those with lung metastasis were more likely to be older, female, black, higher tumor grade, HR−/HER2+, HR+/HER2+, and triple-negative subtypes at diagnosis.[12] Isolated pulmonary metastasis is rare. Research reveals that synchronous metastasis after surgery, survival is from 40% to 50% utilizing all the systemic treatment options. In some studies, the survival of 36 % compared with 11% was reported in those without surgery. Solitary metastasis developing during treatment requires surgical removal, as they most likely represent secondary tumors, especially if there are no extrathoracic tumors.

Head neck cancers: Survival of 20% to 59% is reported after surgery. Due to the high co-incidence of lung cancer and head/neck cancer, even after biopsy, it is not possible to differentiate between metastatic and primary lung cancer. 

Melanoma: 70% of melanomas are metastatic, but only 10% involve the lungs. After surgery, a 5-year survival range from 21% to 35 %.

Non-seminomatous germ cell tumors: All lesions remaining after chemotherapy (cisplatin-based) require removal via surgery. Normalization of tumor markers after chemotherapy does not indicate that residual tumor should not get removed.

Indications for Removal

1. All residual tumor after chemotherapy and normalization of tumor markers
2. Recurrence after chemotherapy treatment
3. Failure to respond to chemotherapy
4. Partial response to chemotherapy

Soft tissue sarcoma: Usually, these are discovered as metachronous metastasis during the course of the disease. Should be treated surgically, given the metastasis are only moderately chemosensitive. The 5-year survival after surgery is reportedly between 29 and 52%.

Osteosarcoma: Despite combined chemotherapy, surgery, radiotherapy, the 5-yrs survival of these patients ranges from 40% to 20%. Primary metastatic osteosarcoma carries a poor prognosis. When discovered synchronous during treatment, the aim of surgery should be complete metastasis removal after chemo and surgical removal of the primary tumor. In the case of recurrent pulmonary metastasis, repeat surgery is necessary irrespective of whether or not there is also chemotherapy. In the case of other primary tumors, surgical options should occur if it is feasible. The primary site is either removed or under control, and other local or systemic treatment options are futile.[13]

Hepatocellular carcinoma (HCC): The successful treatment of multiple lung metastases after hepatic resection for HCC with combined docetaxel, cisplatin (CDDP), and enteric-coated tegafur/uracil (UFT-E) is reported in a study.[14]

SRC kinase inhibitor ( saracatinib) was studied as it inhibits the SRC kinase and their downstream signals (FAK and Stat3). In the orthotopic xenograft HCC model, saracatinib inhibited lung metastasis without influencing primary tumor inhibition. It was able to completely block lung metastasis, indicating the involvement of more complex mechanisms in HCC metastasis to the lung.[15]

Chondrosarcoma: Metastasectomy and radiofrequency ablation (RFA) affect the patient's prognosis with chondrosarcoma of the extremities who develop lung metastasis. Extrapulmonary metastasis and poor grade of tumors affect the prognosis. Three and 5-year survival after lung metastasis is 51.5% and 45.7%. Surgical options merit consideration if extrapulmonary metastasis is under control. RFA is safe, with the local rate of control reported to be 89% to 95% can be repeated if needed. It’s useful in controlling metastatic disease. However, it is less effective if the size of metastasis is greater than 3 cm and if it is near a large segmental vessel.[16]

Forty-two patients were analyzed after metastasectomy for various tumors and were followed for 6 to 98 months; the 3-year and 5-year overall survival rates were 45.7% and 34.6%, respectively, much higher than the postoperative survival rates for stage IIIA non-small cell lung cancer (NSCLC 24.9% to 33%).

A study revealed lymph-node metastases as significant prognostic factors (P < 0.05), with the 5-year survival rates 46.9% and 25.0%, respectively. Previous studies also indicated a significant difference between the lymph-node dissection negative and positive groups in 3-year survival rates. Therefore, systematic mediastinal lymph-node dissections should take place for prognostic purposes during pulmonary metastasectomies. Better prognoses are possible in patients undergoing lymph-node dissections while receiving resections of metastatic lung tumors compared with those who did not undergo hilar or mediastinal lymph-node dissections, suggesting that lymph-node dissection should be mandatory for patients with hilar or mediastinal metastasis.[16]

A study reported that 5-year overall survival rates of 31.4% and 36.6% without and with postoperative treatment, indicating that only a weak relation between postoperative chemotherapy or radiotherapy and overall survival is present.

The study also indicated no significant difference in the effects of surgical resection between patients with unilateral or bilateral multiple metastatic lung tumors compared with solitary unilateral metastatic lung tumors. Patients who succumbed to death after surgery from multiple lung metastases were also had metastases to other organs, including bone, liver, and brain. A detailed examination of other organs is essential for patients with multiple metastases to exclude extrapulmonary metastasis before embarking on surgery.[17][3]

Radiation Oncology

Radiofrequency ablation ( RFA) is useful in cases where surgery is not feasible for pulmonary metastasis.

Colorectal Cancer

About 20% of the patients with colorectal cancer will develop lung metastasis, with 7% developing isolated lung metastasis. Without treatment, median survival is eight months, and 1-year survival is 30%. Patients who undergo surgical resection have a median survival of 36 to 50 months with a 5-year survival of 36% to 67.8%. After surgery, the recurrence rate is 68%, with the lung being the most common site of recurrence. The median survival duration from colorectal cancer treated with radiofrequency ablation is  33 to 67 months; the one, three, and five-year survival rates are 83.9% to 95%, 46 to 76.1%, and 35% to 56%, respectively. The local recurrence rate is 13% to 38%. Therefore, ablation therapy can achieve similarly efficient results as surgical resection. Meanwhile, RFA and surgery both provide similar survival predictors, including the number of lung metastases, whether to perform R0 (clean margins) resection, preoperative ACE levels, and whether thoracic lymph node metastasis has developed.

Of note, pulmonary metastasis from colorectal carcinoma treated with radiofrequency ablation (RFA) is not removable by surgery.

RFA  does less harm to the healthy lung tissue, does not cause changes in lung function, and RFA is repeatable on the same or different lung metastases. A trial of 17 patients with colorectal carcinoma with pulmonary metastasis treated with RFA combined with systemic chemotherapy (n = 10) compared with systemic chemotherapy alone (n= 7). The median survival duration of RFA combined with systemic chemotherapy versus systemic chemotherapy alone was 44.2 vs. 24.7, and the three-year survival rates were 87.5% vs. 33.3% (P = 0.0041). Ablation therapy combined with systemic chemotherapy was superior to chemotherapy alone for the treatment of pulmonary metastasis in colorectal carcinoma. It eliminates colorectal metastasis to the lung and prolongs patient survival.

Bone and soft tissue sarcoma: Around 10% to 15% of osteosarcoma and 20% of soft tissue sarcoma patients have developed distant metastases by the time of diagnosis, and lung metastases account for 85%. Despite recent chemotherapy regimens, there has not been any effective chemotherapy treatment recommended. Due to the conventional dosage of radiotherapy being too severe, stereotactic radiotherapy has been used to control the local disease with 1, 2, 3-year local control rate 94%, 86%, and 82% with a survival rate at 1 and 2 years 76% and 43%. Surgery resection three and 5-year survival rates range from 25 to 54% and 14 to 25%, but only 25 to 30% are operable with a recurrence rate of 40 to 80%. Higher perioperative mortality from surgery is reported in old patients.

Radiofrequency ablation has been minimally invasive, is a good alternative with favorable results proven in different studies. RFA in 29 patients with lung metastases from sarcoma with one and three-year survival rates were 92%  and  63%,  respectively. A report on 21 patients with lung metastases from sarcoma that underwent RFA showed that two and three-year survival rates were 94% and 85%, respectively.

Renal Cancer

Roughly 25% to 30% of patients have distant metastases at the time of diagnosis, and the lung is the most common site of metastasis. Lung metastases from renal cancer are not sensitive to traditional radiotherapy and chemotherapy. The median survival duration is only 8 to 12 months, and the 5-year survival rate is only 2 to 3%.

Treatment with IL-2 and IFN-alpha based immunotherapy is effective in less than 20% of patients with an overall median survival duration is only 13.3 months. With the emergence of molecular targeted therapy, sorafenib is one of the preferred treatments for advanced renal cell carcinoma. Overall survival in the sorafenib group was significantly higher than in the placebo group  (17.8  vs. 14.3 months, hazard ratio 0.78; P = 0.0287). Drug side effects and resistance usually result in the early termination of treatment.

Surgical resection is an effective method for treating lung metastasis from renal carcinoma, with the five-year survival rate ranging from 31 to 40%.  Surgical resection in 48 patients with lung metastases from renal cancer yielded 3, 5, and 10-year survival rates of 60%, 47%, and 18%, respectively.  Another study performed surgical resection in 224 patients with lung metastases from renal cancer with 5-year tumor-specific survival rates of the complete resection (n= 49), and palliative resection (n = 175) groups were 73.6% and 19%, respectively.

In recent years, ablation therapy has been attempted to treat lung metastasis from renal cancer. A study reported a five-year survival rate of 53.8% in 68 patients with lung metastases from renal cancer. Soget al. used RFA to treat 39 patients with lung metastases from renal cancer though significant differences in the overall survival rates between the curative and palliative groups at one (100% vs. 90%), three (100% vs. 52%), and five (100% vs. 52%) years (P < 0.05).

Hepatocellular Carcinoma (HCC)

Being asymptomatic at the initial presentation results in late diagnosis, and cancer diagnosis occurs at an advanced stage. The incidence of lung metastases from primary liver cancer is as high as 20% or more and reaches 40 to 73% in the autopsy.   

Sorafenib is the preferred treatment for lung metastases from primary liver cancer. Limitations for treatment include low response rate, severe adverse reactions, and high cost.

Surgical resection of lung metastases from liver cancer can significantly improve patient survival. In a study of 280 patients with lung metastases from liver cancer, the median survival duration was 40.36 with 1, 3, and 5-year survival rate of 86.7%, 53.9%, 31.8%, and 26.9%, respectively. In the unresectable groups, the median survival was 7.46 months, and the one, three, five, and 10-year survival rates were and 34.1%, 8.1%, 3.5%, and 2.1%. In most cases, due to liver cirrhosis, the patient’s liver function is so poor that they cannot tolerate surgical treatment for lung metastasis.      

In a study of 83 lung metastases in 32 liver cancer cases, were treated with RFA, and the one, two, and three-year survival rates were 83%, 57%, and 57%, respectively. Another study involves performing  RFA for 68 lung metastases in 29 liver cancer patients, and the one, two, and three-year survival rates were 73.1%, 41.1%, and 30%, respectively. Hence  RFA is a good alternative for patients who are not surgical candidates. 

Ablation therapy for lung metastasis from nasopharyngeal cancer: Microwave ablation of 29 lung metastases in 17 patients with nasopharyngeal cancer was performed with complete ablation achieved in 27 patients. New lung metastases only occurred in five patients in a one-year follow-up period.  A study indicated that the median survival duration of nasopharyngeal cancer patients with lung metastasis (10 pts) treated with RFA combined with chemotherapy was significantly longer than those who received chemotherapy alone (77.1  vs.  32.4 months, respectively( P= 0.009).[18] 

Stereotactic radiotherapy is another modality used if tumors are unresectable functionally. Using a dose of more than 100 Gy in 1-5 dose fractions. Even in cancers, e.g., metastatic melanoma and renal cell carcinoma, which are usually considered radioresistant, reports show 88% local control at 18 months. 

Medical Oncology

The treatment of lung metastases depends on the primary tumor of origin. The choice of treatment regimens will be to target the primary tumor cells to treat distant metastasis. 

Staging

Stage IV for most tumors, as distant metastasis to the lung categorizes them stage IV.

Prognosis

Based on the type of tumor, molecular biomarkers, extent of the disease, treatment modalities performed, the prognosis of lung metastasis varies greatly.

Colorectal cancer: Without treatment, median survival is eight months, and 1-year survival is 30%.

Hepatocellular carcinoma: In the unresectable groups, the median survival was 7.46 months, and the one, three, five, and 10-year survival rates were and 34.1%, 8.1%, 3.5%, and 2.1%.

Renal cell cancer: The median survival duration is only 8 to 12 months, and the 5-year survival rate is only 2 to 3%.

Chondrosarcoma: 3 and 5 yrs survival after lung metastasis is 51.5 % and 45.7%.

Breast cancer: The median survival of patients with lung metastases was 21 months, while those with metastases confined to lungs had a median survival of 25 months. In another study, the median overall survival was 22.5 months for breast cancer patients with metastases confined to lungs treated with systemic chemotherapy. However, patients with metastases confined to lungs undergoing pulmonary metastasectomy had a median survival of 35 to 75.6 months with a 5-year overall survival rate of 38% to 54%. Survival analysis showed that the aged, black race, HR−/HER2+, triple-negative subtype, higher grade were the independent risk factor for BCLM patients’ survival, while HR+/HER2+ subtype, insured status, and married status suggested a better prognosis. 

Melanoma: The mean survival of metastatic melanoma is only 6 to 8 months, and the 5-year survival rate is about 5%. The most common metastatic organ is the lung in 40% of cases. Complete resection is beneficial and associated with a 5-year survival rate as high as 39%, compared to a 3% to 5% 5-year survival rate for systemic therapy patients.

Non-seminomatous germ cell tumors: Overall median survival after postchemotherapy surgical removal was 23.4 years. Tumors included teratoma (52.7%), persistent NSGCT (15.0%), and degenerative non-germ cell cancer (10.1%).

Ovarian cancer: In a study on 357 patients, thoracic involvement by tumor was present in 169 patients (44.5%), and 5.6% were alive after five years compared with 49% of patients with no evidence of thoracic involvement. Another study in 255 patients with ovarian epithelial carcinoma showed that 38% had distant metastasis with a median survival from the time of diagnosis of the effusion being six months. Parenchymal lung metastases were present in 7.1% of patients with median survival, eight months.[19][20]

Complications

Chemotherapy Side Effects

Acute side effects mentioned by patients while using chemotherapy for different (breast, colorectal, lung) cancers include chest pain, constipation, diarrhea, dyspnea, fatigue, mucositis, pain, rash, vomiting, anemia.[21]

• Oral and gastrointestinal mucositis may cause local ulceration and pain, which in turn may lead to anorexia, malabsorption, weight loss, anemia, fatigue, and increased risk of sepsis.
• Many anti-cancer drugs can cause chemotherapy-induced peripheral neuropathy (CIPN), including platinum-based agents, vinca alkaloids, taxanes, and proteasome and angiogenesis inhibitors.
• Liver and bone marrow toxicity 
• Muscle wasting, muscle collagen deposition, and changes in muscle mitochondrial function (seen with oxaliplatin)[22] 

Postsurgical Complications

Based on a retrospective analysis of 776 thoracotomies following results were found. The postoperative complication rate was 9.3%.

• Infection n=19
• Atelectasis n=29
• Cardiac arrhythmia n=18
• Stroke n=2
• Myocardial infarction n=3
• Prolonged air leak ( more than three days) n=28
• Renal failure
• The 30-day mortality rate was 0.2% (n=2, due to respiratory failure and stroke).[23]

Radiation Side Effects

• Radiation pneumonitis
• Post-radiation tumors

Consultations

Oncology, pathologist, pulmonologist, cardiothoracic surgeon, radiation oncologist, an interventional radiologist.

Deterrence and Patient Education

Patient education should focus on compliance with follow up screenings and treatments to ensure optimal outcomes. 

Pearls and Other Issues

Phospholipase A2 inhibitors ( PLA2) have been proposed as anticancer drugs because inhibition of PLA2 could theoretically decrease the production of several metabolites implicated in cancer progression. Platelet-activating factor (PAF) receptors' role has been discussed in many study groups to prevent metastasis of breast cancer, ovarian cancer, and melanoma to the lung.[24]

Long non-coding RNAs can be potential therapeutic or diagnostic markers for lung cancer metastasis.[25]

Bergamottin is a naturally occurring furanocoumarin and is known to inhibit the growth of tumor cells. It can block EMT and cause downregulation of fibronectin, vimentin, N-cadherin, twist and snail expression, and cause upregulation of occludin and E-cadherin. The treatment also inhibits multiple oncogenic cascades, such as PI3K/Akt/mTOR. The results demonstrate the possible antimetastatic activity of bergamottin against lung cancer cells.[26]

Fronodoside A, a triterpenoid glycoside isolated from Atlantic cucumber, has been studied to prevent the progression of lung cancer invasion, metastasis in-vivo and in-vitro. Research has found it to potentiate the effects of cisplatin chemotherapy agents.[27]

Enhancing Healthcare Team Outcomes

Treatment of metastatic lung lesions is a combined interprofessional team effort. It requires collaboration between oncologists and other specialists such as pathologists, pulmonologists, cardiothoracic surgeons, radiation oncologists, and interventional radiologists before a successful treatment plan can be outlined and carried out for the patient benefit. Oncology nurses and pharmacists are invaluable in providing ongoing care. Board-certified oncology pharmacists review medication for the dose and interactions and discuss various chemotherapy regimens with the oncologist. They provide education to patients and their families regarding how the drugs work and the adverse effects. Oncology nurses administer treatment, monitor patients for both effectiveness of therapy and adverse events, provide symptomatic care following chemotherapy, counsel the patients and their families, and inform the team of changes in patient status. This interprofessional collaboration will result in better patient outcomes for metastatic disease. [Level 5]