Lung Carcinoma

Respiratory epithelial cells require prolonged exposure to cancer-promoting agents and accumulation of multiple genetic mutations before becoming neoplastic (an effect called field carcinogenesis).

In some patients with lung cancer, secondary or additional mutations in genes that stimulate cell growth (KRAS, MYC) or cause abnormalities in growth factor receptor signaling (EGFR, HER2) can contribute to the uncontrolled proliferation of abnormal cells.

In addition, mutations that inhibit tumor-suppressor genes (eg, TP53, APC) can lead to cancer. Other mutations that may be responsible include the EML4-ALK translocation and mutations in ROS1, BRAF, and PIK3CA.

Genes such as these that are primarily responsible for lung cancer are called oncogenic driver mutations. Although oncogenic driver mutations can cause or contribute to lung cancer among people who smoke, these mutations are particularly likely to be a cause of lung cancer among people who have never smoked. In 2014, the Lung Cancer Mutation Consortium (LCMC) found driver mutations in 64% of 733 lung cancers. This group included people who smoke and people who do not smoke (25% KRAS mutations, 17% EGFR mutations, 8% EML-4-ALK mutations, and 2% BRAF mutations [3]). The second LCMC study accrued 904 patients with stage IV lung cancer who had at least one 14 cancer-related gene tested for and found that oncogenic driver mutations were present in more than half of the patients with adenocarcinoma and that targeted therapies improved survival (4). Additional mutations are being reported, and novel therapies aimed at oncogenic driver mutations are an area of active research.

1. 1.  Division of Cancer Prevention and Control, Centers for Disease Control and Prevention: What Are the Risk Factors for Lung Cancer? Reviewed October 25, 2022. Accessed April 24, 2023

2. 2. U.S. Cancer Statistics Working Group: U.S. Cancer Statistics Data Visualizations Tool, based on 2021 submission data (1999-2019): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; https://www.cdc.gov/cancer/dataviz, released in November 2022

3. 3. Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311 (19):1998–2006, 2014. doi: 10.1001/jama.2014.3741

4. 4. Aisner DL, Sholl LM, Berry LD, et al: The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2). Clin Cancer Res 24(5):1038-1047, 2018. doi:10.1158/1078-0432.CCR-17-2289

The local tumor can cause cough. Less commonly, local tumor causes dyspnea due to airway obstruction, postobstructive atelectasis, or pneumonia and parenchymal loss due to lymphangitic spread. Fever may occur with postobstructive pneumonia. Up to half of patients report vague or localized chest pain. Hemoptysis is less common, and blood loss is minimal, except in rare instances when the tumor erodes into a major artery, causing massive hemorrhage and often death by asphyxiation or exsanguination. Hemoptysis is the presenting symptom in about 10% of patients; 20% of patients experience it during the course of their illness.

Regional spread of tumor may cause pleuritic chest pain or dyspnea due to development of a pleural effusion, hoarseness due to tumor encroachment on the recurrent laryngeal nerve, and dyspnea and hypoxia from diaphragmatic paralysis due to involvement of the phrenic nerve.

Superior vena cava (SVC) syndrome results from compression or invasion of the SVC and can cause headache or a sensation of head fullness, facial or upper-extremity swelling, breathlessness when supine, dilated veins in the neck, face, and upper trunk, and facial and truncal flushing (plethora).

Pancoast syndrome occurs when apical tumors, usually NSCLC (Pancoast tumor), invade the brachial plexus, pleura, or ribs, causing shoulder and upper-extremity pain and weakness or atrophy of the ipsilateral hand. Pancoast syndrome can also include Horner syndrome.

Horner syndrome results when the paravertebral sympathetic chain or the cervical stellate ganglion is involved, causing ptosis, miosis, and anhidrosis.

Spread of the tumor to the pericardium may be asymptomatic or lead to constrictive pericarditis or cardiac tamponade.

In rare cases, esophageal compression by the tumor leads to dysphagia.

Superior Vena Cava Syndrome

Image

© Springer Science+Business Media

Metastases eventually cause symptoms that vary by location. Metastases can spread to the

• Liver, causing pain, nausea, early satiety, and ultimately hepatic insufficiency

• Brain, causing behavioral changes, confusion, aphasia, seizures, paresis or paralysis, nausea and vomiting, and ultimately coma and death

• Bones, causing severe pain and pathologic fractures

• Adrenal glands, rarely causing adrenal insufficiency

Paraneoplastic syndromes are symptoms that occur at sites distant from a tumor or its metastases. Common paraneoplastic syndromes in patients with lung cancer include

• Hypercalcemia (in patients with squamous cell carcinoma, which results from the tumor producing parathyroid hormone–related protein, or because of extensive bone metastases that cause production of osteoclast-activating factors )

• Syndrome of inappropriate antidiuretic hormone (SIADH) secretion

• Finger clubbing with or without hypertrophic pulmonary osteoarthropathy

• Hypercoagulability with migratory superficial thrombophlebitis (Trousseau syndrome)

• Myasthenia-like symptoms (Eaton-Lambert syndrome)

• Cushing syndrome

• Various other neurologic syndromes

Other neurologic syndromes include neuropathies, encephalopathies, encephalitides, myelopathies, and cerebellar disease. Mechanisms for neuromuscular syndromes involve tumor expression of autoantigens with production of autoantibodies, but the cause of most other syndromes is unknown.

Chest x-ray is often the initial imaging test. It may show clearly defined abnormalities, such as a single mass, multifocal masses, a solitary pulmonary nodule, an enlarged hilum, a widened mediastinum, tracheobronchial narrowing, atelectasis, nonresolving parenchymal infiltrates, cavitary lesions, or unexplained pleural thickening or effusion. These findings are suggestive but not diagnostic of lung cancer and require follow-up with CT scans or combined PET–CT scans and cytopathologic confirmation.

Primary Lung Cancer

Image

Image courtesy of Anne S. Tsao, MD.

CT shows many characteristic anatomic patterns and appearances that may strongly suggest the diagnosis. If a lesion found on a plain x-ray is highly suggestive of lung cancer (ie, based on risk factors such as age, tobacco use, symptoms), PET–CT may be done to assist in directing the diagnostic evaluation and staging. This study combines anatomic imaging from CT with functional imaging from PET. The PET images can help differentiate inflammatory and malignant processes. Both CT and PET–CT can help direct core needle biopsy of lesions not amenable to bronchoscopic biopsy. These PET images may also detect regional or distant metastatic disease.

The method used to obtain cells or tissue for confirmation depends on the accessibility of tissue and the location of lesions. Cytology of a sputum or pleural fluid sample is the least invasive method to confirm lung cancer diagnosis.

In patients with productive cough, sputum specimens obtained on awakening may contain high concentrations of malignant cells, but yield for this method is < 50% overall.

Pleural fluid is another convenient source of cells; a malignant effusion is a poor prognostic sign and indicates advanced stage disease.

In general, false-negative cytology readings can be minimized by obtaining as large a volume of sputum or pleural fluid as possible early in the day (for sputum samples) and sending the sample to the pathology laboratory immediately to minimize delays in processing because such delays lead to cell breakdown.

Molecular (genetic) studies can be done on paraffin-embedded tumor cell pellets from pleural fluid if the fluid is spun down and the cell pellet preserved in a timely fashion.

Percutaneous biopsy is the next least invasive procedure. It is more useful for metastatic sites (eg, supraclavicular or other peripheral lymph nodes, pleura, liver, adrenals) than for lung lesions. Risks include a 20 to 25% chance of pneumothorax (primarily in patients with significant emphysema) and the risk of obtaining a false-negative result.

A core biopsy is preferable to a fine-needle biopsy because the latter retrieves too little tissue for accurate genetic studies.

Bronchoscopy is the procedure most often used for diagnosing lung cancer. In theory, the procedure of choice for obtaining tissue is the one that is least invasive; however, in practice, bronchoscopy is often done in addition to or instead of less invasive procedures because diagnostic yields are greater and because bronchoscopy is also important for staging. A combination of washings, brushings, and biopsies of visible endobronchial lesions and of paratracheal, subcarinal, mediastinal, and hilar lymph nodes often yields a tissue diagnosis.

Advances in techniques to guide the bronchoscope have increased the diagnostic yield and the accuracy of sampling more peripheral lesions. Endobronchial ultrasound-guided biopsy (EBUS) can be done during bronchoscopy and has an excellent yield. EBUS is currently the preferred method for staging the mediastinum, except in cases where the lymph nodes cannot be sampled due to anatomic considerations. Navigational bronchoscopy is also used to sample more peripheral lesions with improved diagnostic accuracy. Robotic bronchoscopy is also being implemented at certain centers to improve the diagnostic yield and limit the number of thoracic surgical procedures.

Mediastinoscopy had been the standard test for evaluating mediastinal lymph nodes but is a higher risk procedure that is typically used before more extensive thoracic surgical procedures to confirm or exclude the presence of tumor in those few patients with enlarged mediastinal lymph nodes that cannot be sampled by EBUS.

Surgical lung biopsy, done via open thoracotomy or using video or robotic assistance, is indicated when less invasive methods do not provide a diagnosis in patients whose clinical characteristics and radiographic features strongly suggest that the tumor is resectable.

Some components of staging are part of the typical diagnostic evaluation, for example, endobronchial ultrasound-guided biopsy (EBUS) can be used to sample enlarged lymph nodes at the same time a lung lesion is biopsied.

All lung cancer patients need imaging to determine whether the disease has spread. Different combinations of tests can be done. Some tests are done routinely, and others are done depending on whether the results would impact treatment decisions:

• PET or integrated PET–CT

• CT from neck to pelvis and bone scan (done if PET–CT is not available)

• MRI of chest (for tumors near apex or diaphragm to evaluate vascular supply)

• Biopsy of questionable nodes (if PET is indeterminate)

• Head CT or brain MRI

PET scanning is a reasonably accurate, noninvasive test used to identify malignant mediastinal lymph nodes and other distant metastases (metabolic staging). Integrated PET–CT scanning, in which PET and CT images are combined into a single image by scanners in a single gantry, is more accurate for NSCLC staging than CT or PET alone or than visual correlation of the 2 tests. The use of PET and integrated PET–CT is limited by cost, availability, and specificity (ie, the test is quite sensitive and has an excellent negative predictive value, but its positive predictive value is not as high). PET-CT may be used after a procedure such as bronchoscopy or needle biopsy fails to make a diagnosis when clinical suspicion for lung cancer remains high.

If PET–CT is not available, thin-section high-resolution CT (HRCT) from the neck to the upper abdomen (to detect cervical and supraclavicular and hepatic and adrenal metastases) is one of the first staging tests for both SCLC and NSCLC. However, CT often cannot distinguish postinflammatory changes from malignant intrathoracic lymph node enlargement or benign lesions from malignant hepatic or adrenal lesions (distinctions that determine stage). Thus, other tests are usually done when abnormalities are present in these areas.

When PET scan results are indeterminate, bronchoscopy with endobronchial ultrasonography, mediastinoscopy, or video-assisted thoracoscopic surgery (VATS) can be used to biopsy questionable mediastinal lymph nodes. Without PET scanning, hepatic or adrenal lesions must be evaluated by needle biopsy.

MRI of the chest is slightly more accurate than high-chest HRCT for staging apical (Pancoast) tumors and cancers close to the diaphragm (eg, mesothelioma) and provides an evaluation of the vasculature surrounding the tumors. MRI can also help determine if surgical resection can be considered.

Blood tests are usually done. Calcium and alkaline phosphatase levels, if elevated, suggest possible bone metastases. Other blood tests, such as complete blood count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, electrolytes, serum albumin, and creatinine levels, have no role in staging but provide important prognostic information about the patient’s ability to tolerate treatment and may demonstrate the presence of paraneoplastic syndromes.

After diagnosis, all patients with lung cancer should undergo brain imaging; MRI is preferred to CT. Brain imaging is especially necessary in patients with headache or neurologic abnormalities.

Patients with bone pain or elevated serum calcium or alkaline phosphatase levels should undergo PET–CT or radionuclide bone scanning if PET–CT is not available.

1. 1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al: Reduced lung-cancer mortality with low-dose computed tomographic screening. New Engl J Med 365 (5):395–409, 2011. doi: 10.1056/NEJMoa1102873.

2. 2. de Koning HJ, van der Aalst CM, de Jong PA, et al: Reduced lung-cancer mortality With volume CT screening in a randomized trial. New Engl J Med 382:503–513, 2020. doi: 10.1056/NEJMoa1911793

3. 3. US Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. JAMA 325(10):962-970, 2021. doi: 10.1001/jama.2021.1117

SCLC of any stage is typically initially responsive to treatment, but responses are usually short-lived. Chemotherapy, with or without radiation therapy, is given depending on the stage of disease. Immunotherapy may also be used in extensive SCLC. In many patients, chemotherapy prolongs survival and improves quality of life enough to warrant its use. Surgery generally plays no role in treatment of SCLC, although it may be curative in the rare patient who has a small focal tumor without spread (such as a solitary pulmonary nodule) who underwent surgical resection before the tumor was identified as SCLC.

In limited-stage disease, when disease is confined to a hemithorax, radiation therapy further improves clinical outcomes; such response to radiation therapy was the basis for the definition of limited-stage disease. The use of prophylactic cranial irradiation to prevent brain metastases is also advocated in certain cases; micrometastases are common in SCLC, and chemotherapy has less ability to cross the blood-brain barrier.

In extensive-stage disease,

In general, recurrent SCLC carries a poor prognosis, although patients who maintain a good performance status should be offered further treatment in a clinical trial.

Treatment for NSCLC typically involves assessment of eligibility for surgery followed by choice of surgery, chemotherapy (including targeted therapy and immunotherapy), radiation therapy, or a combination of modalities as appropriate, depending on tumor type and stage.

For stage I and II disease, the standard approach is surgical resection with either lobectomy or pneumonectomy combined with mediastinal lymph node sampling or complete lymph node dissection. Lesser resections, including segmentectomy and wedge resection, are considered for patients with poor pulmonary reserve. Surgery is curative in about 55 to 70% of patients with stage I and in 35 to 55% of patients with stage II disease. Outcomes appear better when surgical resection is done by a thoracic oncologic surgeon with expertise in lung cancer (1, 2). Patients with early-stage disease for whom surgery is high risk may instead have local, non-surgical treatment, such as radiation therapy (stereotactic or conventional) or radiofrequency ablation.

Preoperative pulmonary function is assessed. Surgery is done only if patients with NSCLC will have adequate pulmonary reserve once a lobe or lung is resected. Patients with preoperative forced expiratory volume in 1 second (FEV1) > 2 L generally tolerate pneumonectomy. Patients with FEV1 < 2 L should have a quantitative xenon radionuclide perfusion scan to determine the proportion of function they can expect to lose as a result of resection. Postoperative FEV1 can be predicted by multiplying percent perfusion of the nonresected lung by the preoperative FEV1. A predicted FEV1 > 800 mL or > 40% of the predicted normal FEV1 suggests adequate postoperative lung function, although studies of lung volume reduction surgery in patients with COPD (chronic obstructive pulmonary disease) suggest that patients with FEV1 < 800 mL can tolerate resection if the cancer is located in poorly functional, bullous (generally apical) lung regions.

Neoadjuvant (preoperative) chemotherapy

Adjuvant chemotherapy after surgery is now standard practice for patients with stage II or stage III disease and possibly also for patients with stage IB disease and tumors >

Stage III disease is treated with either chemotherapy, radiation therapy, surgery, or a combination of therapies; the sequence and choice of treatment depend on the location of the patient's disease and comorbidities. In general, concurrent chemotherapy, immunotherapy, and radiation therapy are considered standard treatment for unresectable clinically staged IIIA disease, but the survival remains poor (median survival, 10 to 14 months). Patients with stage IIIB disease with contralateral mediastinal nodal disease or supraclavicular nodal disease are offered either radiation therapy or chemotherapy or both. Patients with locally advanced tumors invading the heart, great vessels, mediastinum, or spine usually receive radiation therapy. In some patients (ie, those with T4 N0 M0 tumors), surgical resection with either neoadjuvant or adjuvant combined chemotherapy and radiation therapy may be feasible.

In stage IV disease, prolonging survival and palliation of symptoms are the goals. Chemotherapy, targeted drugs, and radiation therapy may be used to reduce tumor burden, relieve symptoms, and improve quality of life. However, if no mutation treatable with a targeted drug is identified, median survival is only 9 months, and < 25% of patients survive 1 year. Surgical palliative procedures may be required and may include thoracentesis and pleurodesis of recurrent effusions, placement of indwelling pleural drainage catheters, bronchoscopic fulguration of tumors involving the trachea and mainstem bronchi, placement of stents to prevent airway occlusion, and, in some cases, spinal stabilization for impending spinal cord compression.

Clinical Calculators

Predicted Postoperative FEV1 Following Lung Resection Surgery (Anatomic Method)

Clinical Calculators

Predicted Postoperative FEV1 Following Lung Resection Surgery (Perfusion Method)

NSCLC treatment is based on precision medicine. Molecular analysis is done on adenocarcinomas to look for specific mutations that can direct therapy (see table Some Targeted Therapy Drugs for Non–Small Cell Lung Cancer

For tumors bearing an oncogenic driver mutation, targeted treatments are used first. In patients with stage IV disease and sensitive EGFR

Patients who have EML -4-ALK translocations should receive an ALK and ROS1ALK

Patients with BRAF mutations benefit from the BRAF

Treatment options for lung cancer that recurs after definitive treatment vary by location and include repeat chemotherapy or targeted drugs for metastases, radiation therapy for local recurrence or pain caused by metastases, and brachytherapy for endobronchial disease when additional external radiation cannot be tolerated. Rarely, surgical resection of a solitary metastasis or for palliative purposes is considered.

The treatment of a locally recurrent NSCLC follows the same guidelines as for primary tumor stages I to III. If surgery was used initially, radiation therapy is the main modality. If the recurrence manifests as distant metastases, patients are treated as if they have stage IV disease with a focus on palliation.

Treatment for recurrent or metastatic stage IV NSCLC includes chemotherapy or targeted drugs. The choice depends on tumor histology, mutational profile, patient functional status, and patient preference. For example, an EGFREGFR mutations. When NSCLC progresses, repeat biopsies are commonly done to repeat the molecular and PD-L1 analysis, which can guide future treatment.

Asymptomatic malignant pleural effusions require no treatment. Initial treatment of a symptomatic effusion is with thoracentesis> 90% of cases. Pleurodesis can also be done surgically, often with a video-assisted thoracoscopic surgery (VATS) procedure.

Treatment of superior vena cava syndrome is the same as treatment of lung cancer, with chemotherapy (SCLC), radiation therapy (NSCLC), or both (NSCLC). Corticosteroids are commonly used but are of unproven benefit.

Treatment of Horner syndrome caused by apical tumors is with surgery with or without preoperative radiation therapy or with radiation therapy with or without adjuvant chemotherapy.

Treatment of paraneoplastic syndromes varies by syndrome.

Based on poor overall survival, the need for end-of-life care should be anticipated. Studies have reported that early palliative care intervention leads to less end-of-life chemotherapy use and may even extend life (ie, by avoiding adverse effects of aggressive treatments).

Symptoms of breathlessness can be treated with supplemental oxygen and bronchodilators. Pre-terminal breathlessness can be treated with opioids.

The care provided by hospice programs is extremely well-accepted by patients and families, yet this intervention is markedly underused.

1. 1. Farjah F, Flum DR, Varghese TK Jr, et al: Surgeon specialty and long-term survival after pulmonary resection for lung cancer. Ann Thorac Surg 87 (4):995–1004, 2009. doi: 10.1016/j.athoracsur.2008.12.030

2. 2. Schipper PH, Diggs BS, Ungerleider RM, Welke KF: The influence of surgeon specialty on outcomes in general thoracic surgery: A national sample 1996 to 2005. Ann Thorac Surg 88 (5):1566–1572, 2009. doi: 10.1016/j.athoracsur.2009.08.055

1. 1. Goldstraw P, Chansky K, Crowley J, et al: The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 11(1):39-51, 2016. doi:10.1016/j.jtho.2015.09.009