Lung cancer or bronchogenic carcinoma refers to tumors originating in the lung parenchyma or within bronchi. It is one of the leading causes of cancer-related deaths in the United States. Since 1987, lung cancer is responsible for more deaths in women than breast cancer. It is estimated that there are 225,000 new cases of lung cancer in the United States annually and approximately 160,000 die because of lung cancer. It is interesting to note that at the beginning of the 20th century, lung cancer was a relatively rare disease. Its dramatic rise in later decades is mostly attributable to the increase in smoking among both males and females.
Smoking is the most common cause of lung cancer. It is estimated that 90% of the cases of lung cancer are attributable to smoking. The risk is highest in males who smoke. The risk is further compounded with exposure to other carcinogens, such as asbestos. There is no correlation between lung cancer and the number of packs smoked per year due to the complex interplay between smoking and environmental and genetic factors. The risk of lung cancer by passive smoking increases by 20% to 30%. Other factors include radiation for non-lung cancer treatment, especially non-Hodgkins lymphoma and breast cancer. Exposure to metals, such as chromium, nickel, and arsenic, and polycyclic aromatic hydrocarbons also is associated with lung cancer. Lung diseases like idiopathic pulmonary fibrosis increase risk of lung cancer independent of smoking.
Lung cancer is the most commonly diagnosed cancer worldwide, accounting for 12.4% of all cancers diagnosed. It also is responsible for the most cancer-related deaths, 17.6%. Historically, the lung cancer epidemic seems to involve the developed world only. Recent data suggest that the incidence of lung cancer is dramatically rising with nearly half of new cases, 49.9%, diagnosed in the under-developed world. In the United States, mortality is high in men compared to women. Overall, there is no difference between blacks and whites, but age-adjusted mortality is higher in black males than their white counterparts. No such distinction exists between black and white women.
The pathophysiology of lung cancer is very complex and incompletely understood. It is hypothesized that repeated exposure to carcinogens, cigarette smoke in-particular, leads to dysplasia of lung epithelium. If the exposure continues, it leads to genetic mutations and affects protein synthesis. This, in turn, disrupts the cell cycle and promotes carcinogenesis. The most common genetic mutations responsible for lung cancer development are MYC, BCL2, and p53 for small cell lung cancer (SCLC) and EGFR, KRAS, and p16 for non-small cell lung cancer (NSCLC).
The broad divisions of SCLC and NSCLC represent more than 95% of all lung cancers.
Small Cell Lung Cancer
Histologically, SCLC is characterized by small cells with scant cytoplasm and no distinct nucleoli. The WHO (World Health Organization) classifies SCLC into three cell subtypes: oat cell, intermediate cell, and combined cell (SCLC with NSCLC component, squamous, or adenocarcinoma).
SCLC is almost usually with smoking. It has a higher doubling time and metastasizes early; therefore, it is always considered a systemic disease on diagnosis. The central nervous system, liver, and bone are the most common sites. Certain tumor markers help differentiate SCLC from NSCLC. The most commonly tested tumor markers are thyroid transcription factor-1, CD56, synaptophysin, and chromogranin. Characteristically, NSCLC is associated with a paraneoplastic syndrome which could be the presenting feature of the disease
Non-Small Cell Lung Cancer
Five Types of NSCLC
Multiple compounds have been implicated as the cause of lung cancer. In reality, it is hard to establish a causal relationship due to a battery of other confounding factors, such as the difference in the quantity of exposure time, smoking status.
Among the chemicals considered responsible, asbestos is only one that has a clear causal relationship with the development of lung cancer.
Asbestos and Lung Cancer
Risk depends on exposure time and type of asbestos. Amphibole fibers confer much higher risk of lung cancer than chrysotile fibers. The risk increases considerably with concurrent smoking. In non-smokers who are exposed to asbestos, there is a six-fold increase in the risk of lung cancer; whereas, in smokers, this risk is 16-fold if a minimum of 20 cigarettes smoked per day and nine-fold increase with less than 20 cigarettes per day. Other compounds that may increase the risk of lung cancer include radon, nickel, cadmium, chromium, silica, and arsenic.
No specific signs and symptoms exist for lung cancer. Most patients already have advanced disease at the time of presentation. Lung cancer symptoms occur due to local effects of the tumor, such as a cough due to bronchial compression by the tumor, due to distant metastasis, stroke-like symptoms secondary to brain metastasis, paraneoplastic syndrome, and kidney stones due to persistent hypercalcemia. Specifically:
Lung cancer is the leading cause of death in both men and women. NSCLC accounts for 85% of diagnosed cases of lung cancer in the United States. The overall goal is a timely diagnosis and accurate staging. As per the American College of Chest Physicians (ACCP) guidelines, the initial evaluation should be complete within 6 weeks in patients with tolerable symptoms and no complications. Only 26% and 8% of cancers are diagnosed at stages I and II, whereas 28% and 38% are diagnosed at stages III and IV respectively. Therefore, curative surgery is an option for a minority of patients.
Lung cancer evaluation can be divided in 2 ways:
Goals of Initial Evaluation
Every patient suspected of having lung cancer should undergo the following tests:
Intravenous (IV) contrast enhancement is preferable as it may distinguish mediastinal invasion of the primary tumor or metastatic lymph nodes from vascular structures.
The major advantage of CT is that it provides an accurate anatomic definition of the tumor within the thorax which helps clinicians to decide the optimal biopsy site.
CT can also identify the following:
The main objective of a CT scan is to identify the extent of the tumor, its anatomical location, and the lymph node involvement. TNM staging relies heavily on lymph node involvement. Therefore, most of the societies in Europe and the United States agree to regard a lymph node of 1 centimeter or more in the short axis to be considered as highly suspicious for malignancy. Lymph nodes can be enlarged secondary to acute inflammation, such as with congestive heart failure exacerbation or recent viral infection. The overall sensitivity and specificity of CT scan to identify malignancy are 55% and 81% respectively. Hence, CT is not a good test for lung cancer staging.
The American College of Chest Physicians (ACCP) has proposed grouping patients based on tumor extent and lymph node involvement. Although CT is not the right staging tool, it helps the clinician select the site for tissue biopsy. In other words, based on these groups, further staging via non-invasive or invasive methods is planned.
PET scanning allows in vivo determination of metabolic and pathologic processes. It provides limited anatomic resolution but does provide information on the metabolic activity of the primary tumor, mediastinal involvement, and potential distant metastases. The new integrated PET/CT scanners have eliminated the problem of unclear anatomy.
The primary advantage of PET scanning is that it has reduced the number of futile thoracotomies by accurately identifying metastasis and thus excluding curative surgery as an option.
PET scan is also helpful in excluding recurrent tumors after initial therapy. It also can identify recurrence versus metabolic changes post radiation therapy. False positives occur in patients with active infection and inflammation with increased glycolysis. In cases of recent lymph node sampling, a PET scan may be falsely positive. False-negative PET scans occur when there are impaired blood flow and low metabolic activity, such as with carcinoid and some adenocarcinomas, and smaller lymph nodes.
PET scan has a sensitivity of 80% and specificity of 88%, which is higher than CT but not sufficient to stage lung cancer on its own. Therefore, the ACCP recommends that, except for group A disease, a positive PET does not obviate the need for lymph node sampling.
After CT and PET scans, the next step is to obtain tissue or pathologic confirmation of malignancy, confirm staging, and histological differentiation of cancer. One of the following procedures achieves this.
CT guided a transthoracic biopsy is an option for peripheral lesions with a low risk of pneumothorax. Certain older procedures, such as Chamberlain procedure, is sometimes required.
This is a bronchoscopic technique in which a miniature convex ultrasound of 7.5 MHZ is attached to the tip of the bronchoscope. It provides direct visualization of structures in the mediastinum or lung parenchyma through the bronchial wall. A biopsy is performed in real time. It mainly is used to sample the mediastinal and hilar lymph nodes. The image can be frozen and measured, and there is also Doppler available to identify blood vessels. It is the procedure of choice for this purpose. CP-EBUS is also the procedure of choice postinduction chemotherapy before surgery to confirm complete remission. CP-EBUS can be used to sample upper and lower paratracheal nodes as well as stations 10, 11 and 12. Stations 3, 5, and 6 are not accessible via CP-EBUS.
Instead of a convex probe, there is a miniature (20 to 30 MHz) probe. The advantages are that smaller lesions or lesions that are more peripheral can be reached, and it provides a 360-degree view of lung parenchyma. A real-time biopsy cannot be performed.
The concept is to construct a navigational map of airways using either CT scan or electromagnetic field. After the map is constructed, the software creates the path to reach the location of the nodule. The bronchoscopist can create the pathway, and the software then navigates the bronchoscopist to the biopsy site.
Endoscopic ultrasonography (EUS) is becoming an increasingly useful tool for the diagnosis and staging of lung cancer. It can sample lymph nodes through the esophageal wall and provides a real-time sampling of stations 2, 4, 7, 8, and 9. The latter 2 stations cannot be sampled by Endobronchial ultrasound (EBUS). It has the same sensitivity and specificity of EUS, 89%, and 100% respectively. There is also a growing trend to combine EBUS and EUS as a minimally invasive technique for lung cancer staging.
Mediastinoscopy was formerly the gold standard for lung cancer diagnosis and staging. Now it is mainly used to sample lymph nodes after negative needle technique and when the patient is still at high risk for cancer due to lymph node size or FDG uptake on PET scan. Most commonly, para-tracheal lymph nodes are sampled. Alternatively, an anterior mediastinoscopy (Chamberlain procedure) can be performed to access subaortic and para-aortic nodes, stations 5 and 6 respectively. Mediastinoscopy has a sensitivity of 78% and specificity of 100%. Like all surgical procedures, mediastinoscopy has some risks. General anesthesia is required, and the procedure carries a mortality risk of 0.08%.
Traditionally, thoracoscopy was performed by dividing the ribs and opening the chest cavity. Like laparoscopic surgery, it has largely replaced open abdominal surgeries. Video-assisted thoracoscopy surgery (VATS) has replaced thoracoscopy. It is used to treat a number of chest wall, pleural, pulmonary, and mediastinal conditions. Mediastinal lymph node sampling, as well as full dissection during lung resection for cancer, can be performed with VATS. A newer version of VATS is called RATS (robotic-assisted thoracoscopy). There are no trials comparing VATS and RATS for mediastinal lymph node biopsy.
Treatment of Non-Small Cell Lung Cancer
Surgery is the mainstay of treating stage 1 NSCLC. The procedure of choice is either lobectomy or pneumonectomy with mediastinal lymph node sampling. The 5-year survival is 78% for IA and 53% for IB disease. In patients who do not have the pulmonary reserve to tolerate pneumonectomy or lobectomy, a more conservative approach with wedge resection or segmentectomy can be done. The disadvantage is a higher local recurrence rate, but survival is the same. Local postoperative radiation therapy or adjuvant chemotherapy has not shown to improve outcomes in stage I disease.
The survival of stage IIA and IIB lung is 46% and 36% respectively. The preferred treatment is surgery followed by adjuvant chemotherapy.
If the tumor has invaded the chest wall, then an en-bloc resection of the chest wall is recommended. Pancoast tumor is a unique tumor of stage II. It arises from the superior sulcus and usually diagnosed at a higher stage, IIB or IIIA. The treatment of choice in cases of Pancoast tumor is neoadjuvant chemotherapy usually with etoposide and cisplatin and concurrent radiotherapy followed by resection. Overall survival is 44% to 54% depending on postsurgery presence or absence of microscopic disease in the resected specimen.
This is the most heterogeneous group, consisting of a wide variation of tumor invasion as well as lymph node involvement.
Stage IIIA disease with N1 lymph nodes surgery with curative intent is the treatment of choice. Unfortunately, a significant number of patients are found to have an N2 disease at the time of resection. The current consensus is to perform surgery as planned followed by adjuvant chemotherapy. For patients with stage IIIA tumors with N2/N3 lymph nodes, there is no agreement on treatment. If the patient has good performance status and no weigh-loss, then concurrent chemo-radiotherapy affords the best outcome. However, concurrent chemo-radiotherapy is not as tolerated and can cause severe esophagitis. Sequential therapy is better tolerated. Survival is 40% to 45% in the first two years, but five-year survival is only 20%.
T4 tumors are usually treated exclusively with chemoradiation. Surgery may be an option in T4 N0-1 tumors with carinal involvement. The operative mortality of carinal resection is 10% to 15%, and survival is approximately 20%. If a tumor is T4 due to ipsilateral nonprimary lobe nodules with no mediastinal involvement, then surgery alone renders five-year survival of 20%
Stage IIIB tumors are treated the same way unresectable IIIA cancers are treated, with concurrent chemoradiotherapy. For a select few patients postinduction chemoradiotherapy, surgery might be an option. The trials on the survival of patients with IIIB tumors also included inoperable IIIA tumors; therefore, the survival in IIIB patients is not known.
Stage IV disease is considered incurable, and therapy is aimed at improving survival and alleviating symptoms. Only 10% to 30% of patients respond to chemotherapy, and only 1% to 3% survive 5 years after diagnosis. Single or double drug-based chemotherapy is offered to patients with functional performance status. There is a small survival benefit from chemotherapy.
In highly select patients, non-squamous NSCLC without brain metastasis or hemoptysis might benefit from the addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor.
Targeted therapy for NSCLC
In the early 2000s, researchers discovered that specific mutations encode for proteins that are critical for cell growth and replication. These mutations were named “driver mutations.” It was proposed that blocking these mutation’s pathways may improve survival in lung cancer patients. The current practice is to check for the following mutations in every advanced NSCLC. Each of these mutations has a specific inhibitor available:
Immunotherapy for NSCLC
Immunotherapy, in a simple version, boost the immune system and helps the immune system recognize cancer cells as foreign and increase its responsiveness. There are several check-points to decrease autoimmunity and autodestruction of the body’s cells by the immune system. Malignant cells co-opt these check-points and create tolerance in the immune system.
Of these check-points, programmed-death receptor 1 (PD-1) is of particular interest recently. PD-1 plays an important role in down-regulating T-cells and promotes self-tolerance. However, it also renders the immune system less effective against tumor cells. PD-1 interacts with two proteins: PD-L1 and PD-L2. This binding results in the inactivation of activated T-cells.
At the moment, there are antibodies approved for PD-1 and its ligand, PD-L1 only. They inhibit the PD-1 receptor directly or bind to PD-L1 thus preventing it from inactivating the activated T-cell.
It is an IgG4 monoclonal antibody against PD-1. It is approved by the FDA for squamous and non-squamous NSCLC that has progressed after platinum-based chemotherapy. It can be used in patients with high or low PD-L1 expression status.
It is also an IgG4 monoclonal antibody against PD-1. It is approved for pre-treated metastatic NSCLC with greater than 50% expression of PD-L1 and does not harbor EGFR and ALK mutations. It is also used in combination with pemetrexed and carboplatin for metastatic non-squamous NSCLC with less than 50% expression of PD-L1.
It is an IgG1 antibody against PD-L1. It is approved for use in metastatic, progressive NSCLC during or following treatment with platinum-based chemotherapy. It can be used in patients who express EGFR and ALK mutations and fail targeted therapy.
It is not considered immune therapy. It is an anti-angiogenesis antibody that inhibits vascular endothelial growth factor A (VEGF-A). It is primarily used in combination with platinum-based chemotherapy for the treatment of non-squamous NSCLC. It is contraindicated in squamous cell NSCLC due to the risk of severe and often fatal hemoptysis. It is also used to treat breast, renal, colon, and brain cancers.
Small Cell Lung Cancer Treatment
SCLC is very sensitive to chemotherapy, but unfortunately, has a very high recurrence rate. Treatment for SCLC is according to the stage of the disease.
Treatment of limited-stage small cell lung cancer
Stage I limited-stage small cell lung cancer (LS-SCLC) is lobectomy followed by adjuvant chemotherapy. These include SCLC presenting as peripheral nodules without mediastinal or hilar lymphadenopathy. Care should be taken in completely ruling out lymph node involvement, and this is done by PET-CT followed by lymph node sampling by EBUS bronchoscopy or mediastinoscopy even if PET-CT was negative for lymph node size or FDG uptake.
LS-SCLC with mediastinal or hilar lymph node involvement is 4 to 6 cycles of chemotherapy followed by radiation therapy. Radiation therapy is indicated to avoid recurrence since nearly 80% of SCLC will recur locally without radiation therapy. There are multiple approaches to treatment, including concurrent and alternate chemoradiotherapy or sequential treatments. Concurrent and alternative paths have slightly better outcomes, although they are more toxic than other approaches. Sequential therapy is much better tolerated.
In patients who achieve remission, prophylactic whole brain radiation is also done. This significantly reduces symptomatic brain metastasis and increases overall survival.
Treatment of extensive stage small cell lung cancer (ES-SCLC)
Extensive stage small cell lung cancer (ES-SCLC) includes distant metastasis, malignant pleural or pericardial effusions, contralateral hilar, or supraclavicular lymph node involvement.
Treatment is with platinum-based chemotherapy. Up to 50% to 60% of patients show remission and should be offered radiation therapy followed by prophylactic whole-brain irradiation. Median survival from the time of diagnosis of ES-SCLC is only 8 to 13 months, and only about 5% of patients survive two years postdiagnosis.
Lung Cancer Staging
After the diagnosis of lung cancer, the most crucial step is to stage the disease because the state dictates treatment options, morbidity, and survival. It is of paramount importance that this is done with utmost vigilance. Staging is primarily done for NSCLC using the TNM classification. SCLC also can be staged in the same way, but a much more straightforward approach is used for limited disease and extensive disease.
Tumor, node, metastasis staging of non-small cell lung cancer
Tumor (T), node (N), and metastasis (M) is an internationally accepted way of staging NSCLC. It is comprehensive in defining tumor size and extent, location, and distant spread which helps clinicians draw meaningful conclusions regarding the best treatment, avoid unnecessary surgeries and provide a timely referral to palliative care if the cure is not an option. Most recent TNM classification is the eighth edition, and it is effective in the United States from January 1, 2018. Outside the United States, it was accepted on January 1, 2017, by Union of International Cancer Control (UICC).
For the eighth edition, Ithe International Association of the Study of Lung Cancer (IASLC) studied and analyzed data from 16 countries including approximately 95,000 patients from 1999 to 2010.
A primary tumor is divided into 5 categories, and each category is then further subdivided depending on the size, location and invasion of surrounding structures by the tumor.
T1 (less than 3 cm)
Also considered T4 tumor if involving heart, esophagus, trachea, carina, mediastinum, great vessels, recurrent laryngeal nerve, spine or tumor nodules in the different ipsilateral lobe. Invasion of Diaphragm is now considered a T4 tumor as compared to a T3 tumor in the seventh edition of TNM classification25.
Thoracic Lymph Nodes
Lung cancer staging also depends upon the extension of cancer to the lymph nodes corresponding to the primary tumor as well as the opposite hemithorax. It is extremely important to rule out lymph node metastasis before attempting curative surgery. Lung resection in itself carries high morbidity and mortality, therefore, should not be attempted if a cure is not possible.
Historically, thoracic lymph nodes were first classified in the 1960s by Naruke. This map was accepted by North America, Europe, and Japan. Later, in the 1980s and early 90s, further refinements were made in response to better imaging and invasive testing improvements. Hence, two lymph node maps gained popularity in North America.
In 1996, the differences in the above 2 were resolved in the form of Mountain-Dressler modification, MD-ATS Map. It was accepted in North America but only sporadically in Europe.
The International Association of Study of Lung Cancer (IASLC) attempted to resolve the differences between the MD-ATS map and the Naruke map. The IASLC lymph node map is now the most widely accepted lymph node classification system utilized all over the world.
Thoracic lymph nodes can be divided into mediastinal or N2 and hilar or N1 lymph nodes. N2 nodes are more important because they differentiate in cancer stages and, therefore, treatment options.
Much care has been taking in defining the N2 nodes in all the lymph node maps. We will attempt to explain the classification under the broad headings of Mediastinal and Hilar groups and then further explain the individual mediastinal stations as per IASLC map.
Mediastinal Lymph Nodes
They are sub-divided into the following groups or stations:
Supraclavicular Nodes (Station 1)
It includes lower cervical, supraclavicular and sternal notch nodes. Lymph nodes are further divided into 1R and 1L corresponding to right and left the side of the body respectively. The distinction between 1R and 1L is an imaginary midline of trachea serves as the boundary. Below station 1, the left tracheal border is considered the boundary is differentiating between right and left sided lymph nodes.
Superior Mediastinal Lymph Nodes (Station 2 to 4)
These lymph nodes occupy the superior mediastinum, hence, named accordingly. They are further subdivided into the following groups:
Upperparatracheall (station 2R and 2L)
From the upper border of manubrium to the intersection of caudal margin of the innominate (left brachiocephalic) vein with the trachea.
Pre-vascular (station 3A)
These nodes are not adjacent to the trachea like the nodes in station 2, but they are anterior to the vessels
Pre-vertebral (station 3P)
Nodes not adjacent to the trachea like the nodes in station 2, but behind the esophagus, which is pre-vertebral
Lower para-tracheal (station 4R and 4L)
Aortic Lymph Nodes (5 and 6)
This group includes:
Sub-aortic nodes (station 5)
These nodes are located lateral to the aorta and pulmonary trunk in the so-called AP window
Para-aortic node (station 6)
These are ascending aorta or phrenic nodes lying anterior and lateral to the ascending aorta and the aortic arch
Inferior Mediastinal Lymph Nodes (Station 7 to 9)
This group includes sub-carinal and para-esophageal nodes:
Sub-carinal nodes (station 7)
They extend in a triangular fashion from the division of carina superiorly to the lower border of the bronchus intermedius on the right and the upper border of the lower lobe bronchus on the left.
Para-esophageal nodes (station 8)
These nodes are situated adjacent to the right and left the side of the esophageal wall. Both, station 7 and eight are located below carina.
Pulmonary Ligament (station 9) They are located within the pulmonary ligaments extending from inferior pulmonary vein up to the diaphragm.
Hilar Lymph Nodes (Station 10 to 14)
These are all N1 nodes. These include nodes adjacent to the main stem bronchus and hilar vessels. On the right, they extend from the lower rim of the azygos vein to the interlobar region. On the left from the upper rim of the pulmonary artery to the inter-lobar region.
Lymph Node Classification (N)
N0: No lymph node involvement
N1: Involvement of ipsilateral hilar nodes
N2: Involvement of mediastinal nodes
N3: Involvement of contralateral mediastinal or hilar lymph nodes
Tumor Node Metastasis Staging of Lung Cancer
Occult cancer: TX N0 M0
Primary cancer not found. No lymph node or distant metastasis.
Staging for all Small Cell Lung Cancer
Palliative Care in Lung Cancer
All therapeutic options, surgery, chemotherapy, and radiation have a role in managing pain and other symptoms in terminal lung cancer patients.
Surgery results in better outcomes in patients with at least three months expected survival and good performance status. Surgical procedures for palliation includes tumor bypass procedures, partial resection of the tumor, and removal of metastasis. Surgical intervention may be beneficial in patients with lung cancer if there is airway obstruction, hemoptysis, pleural or pericardial exudate, or metastases to the brain or bone. Almost 30% of lung cancer patients experience central airway occlusion, and bronchoscopic laser destruction followed by stent placement provides immediate relief in such patients.
Chemotherapy helps alleviate symptoms of pain and cough and may prolong survival.
Palliative radiation provides symptomatic relief in 41% to 95% of lung cancer patients. Almost 60% of lung cancer patients, regardless of type and stage, receive radiation treatments during their course of illness. Radiation plays a crucial role in alleviating symptoms of pain due to metastasis, particularly brain and bone metastasis. Endoscopic treatment, such as brachytherapy, helps control symptoms due to airway narrowing.
Lung cancer is best managed with a multidisciplinary team that includes the primary care physician, oncologist, radiologist, radiation therapist, nurse practitioner, thoracic surgeon, palliative care, pain specialist and an internist. Besides urging patients to quit smoking, screening may be useful in selective patients.
Due to high incidence and mortality, there has been a worldwide interest in developing a screening program for lung cancer. A landmark study, the National Lung Screening Trial, showed an overall decrease in mortality of 6.7%. Currently, lung cancer screening is offered to men and women who are 55 years or older who have smoked 30 pack years or more or have quit smoking less than 15 years ago. It is done every year until the minimum age of 74 years.
Lung cancer screening uses a low-dose helical CT scan of the chest which takes less than 25 seconds. A major drawback of screening is the detection of benign lesions, resulting in a relatively high number of unnecessary biopsies, surgeries, or continued radiological follow-up.
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