Non–Small Cell Lung Cancer

Etiology

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.[4] 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.[5][6] 

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.[7] 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.[8][9]

Epidemiology

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.[4] Adenocarcinoma, in particular, is thought to have stemmed from the invention of filter-cigarettes in the 1960s; however, this has not been proven.[10] 

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.[11]

Histopathology

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.[12] 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.[13] 

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.

History and Physical

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.[14] Brain metastasis has the greatest frequency in adenocarcinoma and can present with headache, vomiting, visual field deficit, seizures, or focal neurologic deficits.[15]

Evaluation

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 / Management

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.[16] 

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.[17] Lastly, patients should be actively assessed for eligibility for clinical trials during their disease course.

Differential Diagnosis

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: 

• Bronchogenic carcinoma (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell carcinoma) 
• Metastatic disease from the breast, head/neck, melanoma, colon, kidney, germ cell tumor, sarcoma 
• Pulmonary carcinoid 
• Extranodal lymphoma 
• Plasmacytoma or schwannoma 
• Benign neoplasms such as fibroma, neurofibroma, lipoma, hamartoma, leiomyoma, angioma
• Vascular phenomena such as hematoma, pulmonary infarct, arteriovenous malformation
• Bronchogenic cyst 
• Inflammatory findings such as sarcoidosis, rheumatoid nodule, granulomatosis with polyangiitis 
• Infectious granuloma (histoplasmosis, coccidioidomycosis, tuberculosis, atypical mycobacteria, cryptococcus, blastomycosis)
• Bacterial abscess 
• Aspergillus 
• Pseudotumor 
• Mucoid impaction

Prognosis

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.[18][19] 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.[20] 

Metabolic activity on PET scan has been shown to have a poor prognosis in stages I-IV NSCLC.[21] 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.[22]

Complications

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.[23]  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.