Lung cancer is a diagnosis that approximately 230,000 United States citizens will receive annually. Deaths are estimated at 135,000 patients per year. Lung cancer deaths have become more numerous than the deaths from prostate, breast, brain, and colorectal cancer combined. It has now become the most common cause of cancer deaths in men and the second most common in women. However, this statistic is now declining largely due to anti-smoking campaigns and decreased tobacco use in the United States.
The foundation of lung tumor classification follows the 2015 World Health Organization (WHO) classification of lung tumors. This classification system relies on immunohistochemistry and light microscopy in order to better guide treatment and determine a prognostic course. Non-small cell lung cancer (NSCLC) is a term that includes a variety of different lung cancers, most notably adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common type of lung cancer in this category and includes one-half of all lung cancer cases. Squamous cell carcinoma is another type of NSCLC that had been the most frequently diagnosed lung cancer before this time. Squamous cell carcinoma (SCC) usually originates at the origin of the tracheobronchial tree, but more cases are now diagnosed in the periphery of the lung.
Large cell carcinoma is a subset of NSCLC that is a diagnosis of exclusion. It is poorly differentiated and cannot be further classified by immunohistochemistry (IHC) or electron microscopy. However, 90% of cases will show squamous, glandular, or neuroendocrine differentiation. NSCLC also includes other subsets of lung cancer, with both heterogeneous categories and broad terminology. These include adenosquamous carcinoma, sarcomatoid carcinoma, and non-small cell neuroendocrine tumors.
The etiology of NSCLC can be further categorized into avoidable and unavoidable risk factors. The most well-known avoidable risk factor for NSCLC is inhaled tobacco use. Other causes of lung cancer include alcohol use, environmental exposure to secondhand smoke, asbestos, radon, arsenic, chromium, nickel, as well as exposure to ionizing radiation, and polycyclic aromatic hydrocarbons. Radiation therapy can also cause primary lung cancer when it is utilized for the treatment of other malignancies such as breast cancer and Hodgkin lymphoma.
Patients with pulmonary fibrosis have been found to have an approximately sevenfold increase in the risk of developing lung cancer, and this has been shown to be independent of tobacco use. The incidence of lung cancer in patients with human immunodeficiency virus (HIV) has also been found to be increased compared to the uninfected population, and this has been shown to be independent of smoking status or antiretroviral therapy use in the HIV population.
Tobacco use has been cited as the cause of approximately 90% of all lung cancers. Patients that currently smoke with 40 pack/year smoking history have twenty times the likelihood of developing lung cancer than a non-smoker. This risk can increase if further environmental or lifestyle exposures are compounded with tobacco use, such as asbestos exposure. Adenocarcinoma, in particular, is thought to have stemmed from the invention of filter-cigarettes in the 1960s; however, this has not been proven.
Worldwide, lung cancer is the leading cause of cancer death in men and the second most common in women. There is a wide variation in lung cancer incidence of different populations based on the prevalence of tobacco use in various countries. The incidence of lung cancer directly relates to the increase or decrease in the rate of smoking in different populations. For example, in the United States, the age-adjusted mortality rate is projected to decrease by 79 percent between 2015 and 2065 due to decreased rates of tobacco use and anti-smoking campaigns.
Histologic diagnosis is an important component of a cancer diagnosis. Adenocarcinoma requires evidence of neoplastic gland formation, pneumocyte marker expression in the form of TTF-1 with or without napsin, or intracytoplasmic mucin. The majority of neoplastic gland formation includes acinar, papillary, or micropapillary, leptic, or solid growth pattern. The diagnosis of squamous cell carcinoma relies on the presence of keratin production of tumor cells, which can also include intercellular desmosomes. Immunohistochemistry (IHC) of squamous cell carcinoma reveals expression of p40, p63, CK5, or desmoglein.
As previously described, large cell carcinoma is a diagnosis of exclusion and can demonstrate squamous, glandular, or neuroendocrine differentiation in 90 percent of cases. Poorly differentiated carcinoma is only defined as large cell carcinoma if it does not demonstrate defining IHC markers that would preclude the disease to another subtype of lung cancer.
Clinical manifestations of non-small cell lung cancer can be divided into intrathoracic effects and extrathoracic effects. Intrathoracic effects can include cough, hemoptysis, chest pain, dyspnea, or hoarseness, which can be appreciated on history and physical exam. Squamous cell carcinoma can cause Pancoast syndrome, manifested by pain in the shoulder (but may also include the forearm, scapula, or fingers), Horner syndrome, atrophy of the hand muscles, or bony destruction. Bony metastasis can be suspected during the physical examination as approximately 20 percent of NSCLC have bone metastases on initial presentation. Brain metastasis has the greatest frequency in adenocarcinoma and can present with headache, vomiting, visual field deficit, seizures, or focal neurologic deficits.
Initial evaluation after history and physical exam should include a complete blood count (CBC) as well as a complete metabolic panel (CMP) as this will further evaluate for any potential hematologic or electrolyte sequelae from NSCLC. This could include hypercalcemia or elevated alkaline phosphatase in the setting of bony metastasis. Imaging should begin with a chest radiograph as the presentation of NSCLC can be nonspecific. If lung cancer is suspected, further evaluation with computed tomography (CT) imaging would likely be warranted to further characterize the pathology noted on the chest radiograph.
Tissue biopsy will be needed for histopathologic and immunohistochemistry evaluation to form the diagnosis of NSCLC. Once a diagnosis is made, a CT chest and upper abdomen to include the adrenals should be ordered to assess for metastatic disease, and a positron emission tomography (PET) scan can be utilized to further stage the patient for the extent of disease and treatment. Also, brain magnetic resonance imaging (MRI) is needed to assess for brain metastasis to complete the disease staging.
Treatment varies based on the patient's functional status, comorbidities, tumor stage, and molecular characteristics of the disease. Patients who have stage I, II, or III NSCLC are treated with the intent to cure. This can include surgery, chemotherapy, radiation therapy (RT), or a combined modality approach. Systemic therapy is indicated for those with distant metastases and stage IV disease, or if they recur after initial management. Lobectomy is generally accepted as an approach for surgical intervention on early-stage NSCLC. Patients with clinical stage I or II NSCLC who are surgical candidates are treated initially with resection and subsequent pathologic staging. Based on pathologic staging, surveillance may be indicated if the patient is pathologic stage IA. If found to be pathologic stage IB or stage II/III, the patient may then undergo adjuvant chemotherapy.
If the patient is found to have positive margins, they would then require postoperative radiation therapy or reresection followed by adjuvant chemotherapy. If the patient is a clinical-stage I or II and deemed not a surgical candidate, then treatment would focus on stereotactic body radiation therapy (SBRT) or definitive RT. Clinical stage III would indicate a multidisciplinary approach to treatment that would include consultation with medical oncology, radiation oncology, and thoracic surgery to decide on the optimal combined approach to the disease process. It is important for tissue biopsy to be analyzed for targetable mutation, which can aid in the treatment of patients with stage IV NSCLC. For example, if epidermal growth factor receptor (EGFR) positive, tyrosine kinase inhibitors such as osimertinib, erlotinib, gefitinib, or afatinib can be utilized in treatment. If the tumor contains anaplastic lymphoma kinase (ALK) fusion oncogene, treatment with an ALK tyrosine kinase inhibitor is preferred, which can include alectinib, ceritinib, or brigatinib.
A variety of other mutations, including ROS1, BRAF, RET, TRK, MET, KRAS, can also be found, and for these, their specific inhibitors should be integrated into the treatment plan. If a driver mutation is absent or unknown, the level of programmed cell death ligand 1 (PD-L1) expression should be quantified, and if greater than 50 percent, then pembrolizumab or atezolizumab may be utilized in the treatment plan. These can also be used as single-agent treatment without chemotherapy. Lastly, patients should be actively assessed for eligibility for clinical trials during their disease course.
The diagnosis of NSCLC is usually suspected once the patient is found to have a pulmonary nodule on a chest radiograph after they present with intrathoracic symptoms. Based on the intrathoracic symptoms and the potential chest radiograph findings, the differential diagnosis can, therefore, include:
The prognosis of NSCLC is dependent on the tumor, node, metastasis (TNM) staging, and the performance status/comorbidities of the patient. Patients with poor performance status are associated with shortened survival. Poor appetite and weight loss are also poor prognostic signs. Lymphatic vessel invasion has a negative impact on prognosis, as does occult lymph node metastasis. Patients with actionable mutations have been shown to have a better prognosis. For example, activating EGFR mutations are found in adenocarcinoma associated with never smokers, women, and/or Asian ethnicity and generally have a significantly better prognosis.
Metabolic activity on PET scan has been shown to have a poor prognosis in stages I-IV NSCLC. Recurrence after complete resection has been cited at 41 percent, with the median time to recurrence at 11.5 months and median survival of 8.1 months. Shorter survival depended on performance status, disease-free interval, the involvement of distant metastases, and prior use of neoadjuvant chemotherapy or adjuvant RT.
Complications from NSCLC depend on the local extent of the disease process and the involvement of potential metastases of cancer. Intrathoracic complications can include malignant pleural effusion, which can lead to dyspnea or respiratory failure depending on the extent of the pathology and comorbid conditions. Non-small cell lung cancer is also the most common malignant cause of superior vena cava (SVC) syndrome and accounts for approximately 50 percent of all cases. This usually presents as the gradual onset of face/neck swelling with distended neck veins and upper extremity swelling due to obstruction of blood flow through the superior vena cava.
Patients should be educated on tobacco cessation and avoidance of second-hand smoke. The US Preventative Services Task Force recommends the "5 A's" approach to guide clinicians into a conversation above tobacco cessation. This includes asking about tobacco use, advisement on quitting, assessing readiness for the patient to quit, assisting in tobacco cessation, and arranging to follow up with the patient. Treatment considerations involve behavioral and pharmacologic therapy. This includes behavioral counseling, nicotine gum, lozenges, or a nicotine patch. Bupropion and varenicline are also options for pharmacotherapy used for smoking cessation.
The management of NSCLC depends on an interprofessional approach for the care of the patient. This begins with prevention, in which the primary clinician has an integral role in smoking cessation counseling. The primary clinician also has an integral role in the potential early diagnosis of this disease with lung cancer screening before it evolves to advanced stages where prognosis worsens. Once the diagnosis is made, an interprofessional approach should be utilized with medical oncology, radiation oncology, thoracic surgery, and pathology in order to optimize the patient's treatment plan depending on their TNM staging at the time of diagnosis.
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