Pulmonary Oncology

Lung Cancer: Diagnosis, Treatment Principles, and Screening

KELLY M. LATIMER, MD, MPH, and TIMOTHY F. MOTT, MD, Naval Hospital Pensacola, Pensacola, Florida

Lung cancer is classified histologically into small cell and non–small cell lung cancers. The most common symptoms of lung cancer are cough, dyspnea, hemoptysis, and systemic symptoms such as weight loss and anorexia. High-risk patients who present with symptoms should undergo chest radiography. If a likely alternative diagnosis is not identi-fied, computed tomography and possibly positron emission tomography should be performed. If suspicion for lung cancer is high, a diagnostic evaluation is warranted. The diagnostic evaluation has three simultaneous steps (tissue diagnosis, staging, and functional evaluation), all of which affect treatment planning and determination of prognosis. The least invasive method possible should be used. The diagnostic evaluation and treatment of a patient with lung can-cer require a team of specialists, including a pulmonologist, medical oncologist, radiation oncologist, pathologist, radi-ologist, and thoracic surgeon. Non–small cell lung cancer specimens are tested for various mutations, which, if present, can be treated with new targeted molecular therapies. The family physician should remain involved in the patient’s care to ensure that the values and wishes of the patient and family are considered and, if necessary, to coordinate end-of-life care. Early palliative care improves quality of life and may prolong survival. Family physicians should concentrate on early recognition of lung cancer, as well as prevention by encouraging tobacco cessation at every visit. The U.S. Preventive Services Task Force recommends lung cancer screening using low-dose computed tomography in high-risk patients. However, the American Academy of Family Physicians concludes that the evidence is insufficient to recom-mend for or against screening. Whether to screen high-risk patients should be a shared decision between the physician and patient. (Am Fam Physician. 2015;91(4):250-256. Copyright © 2015 American Academy of Family Physicians.)

CME This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions on page 230.

Author disclosure: No rel-evant financial affiliations.

▲ Patient information: A handout on this topic, written by the authors of this article, is available at http://www.aafp.org/ afp/2015/0215/p250-s1. html.

Scan the QR code below with your mobile device for easy access to the patient information hand-out on the AFP mobile site.

In 2010, approximately 200,000 persons in the United States were diagnosed with lung cancer, and nearly 160,000 persons died of the disease.1,2 The aver-age age at diagnosis is 68 to 70 years.3 Inci-

dence and death rates vary widely among states and regions of the United States, com-mensurate with geographic disparities in tobacco use. Utah has the lowest incidence (28 per 100,000) and Kentucky has the high-est (101 per 100,000).4 The overall incidence of lung cancer declined by 2% between 2005 and 2009.5

Risk Factors

Tobacco use causes 80% to 90% of all lung cancers.6,7 Secondhand tobacco smoke expo-sure is also a significant risk factor, with younger age at exposure associated with higher risk of lung cancer.8 Risk factors (Table 16-14) are typically dose- and duration-dependent, and many carcinogens act syn-ergistically when combined with tobacco smoke.9 For example, arsenic in drinking water has been associated with lung cancer

when combined with exposure to tobacco smoke.10,11 Radon, a naturally occurring radioactive gas found in some homes, is estimated to cause 21,000 cases of lung can-cer per year.12 Any home can have elevated radon levels, but the highest levels are found in the Northern and Midwestern regions of the United States.13 A person’s risk of lung cancer can be calculated using a validated online tool available at http://www.disease riskindex.harvard.edu/update/index.htm.

Etiology

A combination of intrinsic factors and exposure to environmental carcinogens is involved in the pathogenesis of lung cancer.7 Preinvasive lesions such as adenocarcinoma in situ and minimally invasive adenocarci-noma are well described and show that there is likely a stepwise progression from dys-plasia to malignancy.7 Familial and genetic variations can predispose a person to lung cancer, even nonsmokers.

Many genetic mutations within tumors have been identified. For example, mutations

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American Family Physician 251

Initial Evaluation

The initial evaluation of a patient with suspected lung cancer begins with a history and physical examination; complete blood count; measurement of alkaline phos-phatase, hepatic transaminase, and calcium levels; chem-istries (electrolytes, blood urea nitrogen, creatinine); and chest radiography.22 Normal findings on a chest radio-graph do not rule out lung cancer because a small tumor can be hidden within the mediastinum or elsewhere in the chest. If suspicion remains high because a likely alter-native diagnosis is not identified on the chest radiograph, contrast-enhanced computed tomography (CT) should be performed, followed by positron emission tomography if necessary.17,19,22

A multidisciplinary team consisting of a pulmonolo-gist, medical oncologist, radiation oncologist, patholo-gist, radiologist, and thoracic surgeon then plans the diagnostic evaluation, the results of which guide

These symptoms are a result of ectopic pro-duction of hormones from the tumor or the body’s reaction to the tumor, and are not directly attributable to the tumor or metas-tasis. About 10% of patients with lung can-cer present with a paraneoplastic syndrome, and this rate is higher in patients with SCLC.17 The best treatment for paraneoplas-tic syndromes is treatment of the underlying cancer.17 Digital clubbing is a common para-neoplastic syndrome finding that is poorly understood, and it is more common with

NSCLC.

Most data about symptoms at presenta-tion of lung cancer are from referral centers, making extrapolation to the primary care setting difficult.19 Two individual symptoms that significantly increase the likelihood of lung cancer are digital clubbing and hemop-

tysis.18-21 Other independent predictors of lung cancer include loss of appetite, weight loss, fatigue, dyspnea, chest or rib pain, and an increasing number of visits to evaluate persistent cough.18 Patients rarely present with only one symptom, and the positive predictive value is higher when two or more symptoms are reported. For example, the combination of weight loss and hemopty-sis has a positive predictive value of 9.2%.19 Lung can-cer should be highly suspected in any patient older than 40 years with risk factors and symptoms. However, phy-sicians must remember that lung cancer can occur in younger persons and in individuals without known risk factors.

Lung Cancer

Table 1. Risk Factors for Lung Cancer

Relative Relative

Risk factors risk Risk factors risk

Tobacco use or exposure Comorbidities

Current smoking 20 Human 2 to 11

Former smoking 9 immunodeficiency

Secondhand smoke 1.3 virus infection

Idiopathic pulmonary 7

exposure

Environmental exposures fibrosis

Chronic obstructive 2 to 3.1

Asbestos 3

pulmonary disease

Radon 3

Tuberculosis —

Other exposures —

Other

Air pollution

History of chest 5.9

Arsenic

radiotherapy

Beryllium

History of chemotherapy 4.2

Beta-carotene ingestion

Family history of lung 2

Chromium

cancer

Nickel Older age —

Soot

Information from references 6 through 14.

in the epidermal growth factor receptor (EGFR) gene are present in 20% of adenocarcinomas15; patients with this mutation are candidates for targeted molecular therapy with a drug that inhibits EGFR (erlotinib [Tarceva] or afatinib [Gilotrif]) or with a monoclonal antibody against EGFR (cetuximab [Erbitux]).15 Tumor mutations may also predict response to or toxicity from certain chemotherapies and are an important area for future investigation.15

Pathology

Lung cancer is classified by its histologic appearance into small cell lung cancer (SCLC) or non–small cell lung cancer (NSCLC; eTable A). NSCLC is divided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma; these are further subclassified.16 NSCLC is sometimes poorly differentiated and only distinguish-able by immunohistochemical stains and molecular testing. This is problematic when only a small amount of tissue is available for testing. The optimal choice of treatment relies on a complete phenotypic and genotypic characterization of the tumor.

Clinical Presentation

Patients with lung cancer are almost always symptomatic at diagnosis.17 Symptoms can be caused by the primary tumor (e.g., cough, hemoptysis); intrathoracic spread (e.g., Horner syndrome, superior vena cava obstruc-tion); and distant metastases (e.g., bone pain). Tables 218 and 317 summarize these symptoms. Symptoms can also be caused by paraneoplastic syndromes (Table 417), such as the syndrome of inappropriate antidiuretic hormone.

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Lung Cancer

Table 2. Signs and Symptoms of Lung Cancer Due to Local Effects

Sign/symptom of the primary tumor* LR+ LR–

Digital clubbing 55.0 0.96

Hemoptysis 13.2 0.81

Weight loss 6.2 0.76

Loss of appetite 4.8 0.84

Dyspnea 3.6 0.68

Chest or rib pain 3.3 0.52

Fatigue 2.3 0.76

First visit for cough 2.2 0.50

Second visit for cough 3.2 0.66

Third visit for cough 4.2 0.77

Sign/symptom of intrathoracic spread Clinical context

Decreased breath sounds and dyspnea Malignant pleural effusion

Decreased heart sounds and enlarged Malignant pericardial effusion

cardiac silhouette

Dysphagia Esophageal invasion

Elevated hemidiaphragm Phrenic nerve paralysis

Facial swelling, plethora, and upper Superior vena cava syndrome

extremity edema

Hoarseness, weak cough Recurrent laryngeal nerve palsy

Pleuritic chest pain Chest wall invasion

Ptosis, miosis, facial anhidrosis Horner syndrome (sympathetic

chain compression)

Shoulder pain and muscle wasting along Pancoast tumor (superior sulcus

the C8-T3 nerve root tumor)

LR+ = positive likelihood ratio; LR– = negative likelihood ratio.

*—Among patients presenting with lung symptoms, primarily cough.

Information from reference 18.

Table 3. Signs and Symptoms of Lung Cancer Due to Distant Metastases

Site Sign or symptom Frequency (%)

Any site Any sign or symptom 33

Liver Weakness, weight loss, anorexia, hepatomegaly Up to 60

Bone Pain, fracture, elevated alkaline phosphatase Up to 25

Lymphatics Lymphadenopathy 15 to 20

Brain Headaches, seizures, nausea and vomiting, Up to 10

mental status changes

Adrenals Adrenal insufficiency Rare

Skin Subcutaneous nodules Rare

Information from reference 17.

treatment and determine prognosis. The patient’s family physician should remain involved in the patient’s care to ensure that the values and wishes of the patient and fam-ily are considered and, if necessary, to coor-dinate end-of-life care.

Diagnostic Evaluation

The diagnostic evaluation includes three simultaneous steps: tissue diagnosis, staging, and functional evaluation.

TISSUE DIAGNOSIS

Although experienced physicians can often diagnose the type of lung cancer based on clinical presentation and radiographic appearance, an adequate tissue sample is imperative to optimize the diagnosis and plan treatment.22 Molecular testing requires a significant amount of tissue. Targeted therapies can increase treatment options for patients with advanced disease or poor functional status. Molecular testing is also standard in never smokers with squamous cell tumors, making ample tissue all the more essential in such patients.22 For small or peripherally located lung cancers, this can be challenging.

A variety of diagnostic methods are avail-able that yield cytology samples or small biopsies. The choice of procedure depends on the type, location, and size of the tumor; comorbidities; and accessibility of metasta-ses (Table 5).22-24 In general, the least invasive method possible should be used.22 If the pro-cedure fails to obtain tissue, a more invasive method is needed. Conventional bronchos-copy works best for central lesions, whereas CT-guided transthoracic needle aspiration is typically the first-line method for periph-eral lesions. Endobronchial ultrasound24 and electromagnetic navigation23 are some of the newer procedures that may increase the diagnostic yield of bronchoscopy for select patients with mediastinal or peripheral lesions.24

STAGING

Clinical staging is based on all informa-tion obtained before treatment, including findings from CT and positron emission

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Lung Cancer

Oncology Group Performance Status is

Table 4. Paraneoplastic Syndromes Associated an easy-to-use grading tool to predict how

with Lung Cancer well patients will tolerate chemotherapy 29:

• 0: Fully active, able to carry on predis-

Frequency

ease activity without restriction

Syndrome (%) Comments • 1: Restricted in physically strenuous

Systemic (anorexia, cachexia, 0 to 68 May be readily apparent and striking activity but ambulatory and able to

weight loss, fatigue, fever) perform light or sedentary work (e.g.,

Digital clubbing 29 More common with non–small cell light housework, office work)

lung cancer • 2: Ambulatory and capable of all self-

Hypercalcemia 10 to 20 Ectopic production of parathyroid

care but unable to carry out any work

hormone–related peptide; may be

activities, up and about more than

life-threatening

50% of waking hours

Hyponatremia 1 to 5 Syndrome of inappropriate antidiuretic •

hormone or ectopic production of 3: Capable of only limited self-care,

atrial natriuretic peptide confined to a bed or chair more than

Paraneoplastic encephalitis 0.2 Mental status changes • 50% of waking hours

Cushing syndrome Rare Ectopic production of 4: Completely disabled, incapable of

adrenocorticotropic hormone

any self-care, totally confined to a bed

Hypertrophic Rare Triad of clubbing, arthralgias, and

or chair

osteoarthropathy ossifying periostitis •

5: Dead

Muscular weakness Rare Lambert-Eaton myasthenic syndrome

Candidates for lung resection need

Information from reference 17. standard preoperative evaluation plus

pulmonary function testing and carbon

monoxide diffusion in the lung measure-

tomography and invasive staging such as mediastinos- ments to estimate postsurgical lung reserve.30 Brain mag-

copy.25 Pathologic staging is performed after surgical netic resonance imaging is standard in the pretreatment

resection and may upgrade or downgrade the clinical evaluation, except in patients with stage IA NSCLC.30

staging. NSCLC is staged according to the TNM (tumor Treatment

size, nodes, metastasis) system. The 7th edition of this

system, which is the most recent, is based on a retro- NON–SMALL CELL LUNG CANCER

spective analysis of more than 81,000 cases of lung The treatment of NSCLC is well detailed in the 2013

cancer collected from around the world between 1990 ACCP evidence-based practice guidelines.31-33 The

and 2000.26,27 An online calculator available at http:// nuances of treatment are evolving, complex, and largely

staginglungcancer.org/calculator summarizes the TNM beyond the scope of this review, yet a few themes are

staging system and provides corresponding drawings, significant. Morbidity and mortality outcomes may be

CT scans, and survival curves. improved for patients evaluated and treated by a surgi-

For SCLC, American College of Chest Physicians cal thoracic oncologist in conjunction with a multidisci-

(ACCP) guidelines recommend using the 7th edition plinary team at a lung cancer treatment center.

TNM staging system for prognosis and placement into Surgical resection is indicated in medically fit patients

clinical trials.25,27 Many physicians use the simpler Vet- with resectable stage I or II NSCLC, preferably a mini-

erans Administration Lung Study Group classification mally invasive approach such as video-assisted thoracic

system to stage SCLC for treatment purposes.28 Limited surgery.31 The goal for stage III infiltrative NSCLC is

disease is cancer confined within a single tolerable radia- eradicating known intrathoracic cancer while dimin-

tion field. Extensive disease is cancer that has extended ishing subsequent intrathoracic and systemic disease,32

outside of a single hemithorax. usually through chemotherapy and radiation based on

FUNCTIONAL CAPACITY tumor histology and the patient’s functional status. In

stage IV tumors, multidisciplinary management options

Patients with advanced age, poor nutritional status, or are also largely dictated by histology and patient status.

multiple comorbidities may not be able to tolerate lung Palliative care should be initiated early in patients with

resection, radiation, or chemotherapy and thus treat- stage IV NSCLC, or at any stage if underlying morbidity

ment must be individualized. The Eastern Cooperative or patient choice prevents intent-to-cure therapy. Early

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Table 5. Methods for Tissue Diagnosis of Lung Cancer

Method* Comments

Biopsy or fine-needle aspiration of Used in the presence of palpable lymph nodes

accessible metastasis or lymph node

Conventional bronchoscopy brushings High sensitivity for central lesions, much lower sensitivity for peripheral lesions

and washings

Computed tomography–guided Good for peripheral lesions seen on computed tomography, associated with pneumothorax,

transthoracic needle aspiration lower sensitivity for smaller lesions

Transbronchial needle aspiration Indicated for central lesions

Electromagnetic navigation Improved diagnostic yield for bronchoscopy of peripheral lesions, requires advanced training

bronchoscopy 23 beyond skill of most bronchoscopists

Endobronchial ultrasound–guided Best for paratracheal, subcarinal, and perihilar nodes, lower sensitivity for peripheral lesions,

transbronchial needle aspiration24 requires advanced training beyond skill of most bronchoscopists

Pleural biopsy Used with pleural effusion and if pleural fluid cytology findings are negative

Sputum cytology Indicated for central lesions, noninvasive, follow-up testing required if findings are negative

Thoracentesis (pleural fluid cytology) Easily accessible if present, ultrasound guidance improves yield and decreases risk of

pneumothorax, second sample increases diagnostic yield

Video-assisted thoracic surgery Used for a small single high-risk nodule

*—Listed from least to most invasive.

Information from references 22 through 24.

palliative care significantly improves quality of life, decreases the incidence of depression in patients with newly diagnosed NSCLC, and may prolong survival.33 Additional management decisions may be influenced by a patient’s involvement in an approved clinical trial.

SMALL CELL LUNG CANCER

Limited stage SCLC is treated with an intent to cure; treatment results in a five-year survival rate of up to 25%.34 For early limited stage SCLC, surgery may be indi-cated. For both limited stage and extensive stage SCLC, concurrent chemotherapy and radiation therapy with a platinum-based agent and at least one other chemothera-peutic agent should be pursued. The five-year survival rate is virtually zero for extensive stage SCLC. As with more extensive NSCLC, a patient’s comorbidities, the extent of disease, and patient preferences are integral to making treatment decisions, and palliative care should be initiated early.

Prognosis

Prognosis is better if presenting symptoms are caused by the primary tumor rather than by metastatic disease or paraneoplastic syndromes.17 It is also better in earlier stages of cancer. Survival rates at five years can be greater than 50% for those with localized disease, but decrease to less than 5% in those with distant disease.4 The online

staging calculator at http://staginglungcancer.org/ calculator can also be used for prognosis.

Screening

The U.S. Preventive Services Task Force (USPSTF) sup-ports annual low-dose CT to screen for lung cancer in patients 55 to 80 years of age with at least a 30 pack-year history who currently smoke or have quit within the past 15 years.35 The USPSTF cites the National Lung Screen-ing Trial, which found a number needed to screen of 312 to prevent one lung cancer death in five years with three screening examinations.36 The recommendation was also based on extensive modeling studies to refine esti-mates of benefit and harm.37 The American Academy of Family Physicians concludes that the evidence is insuf-ficient to recommend for or against low-dose CT screen-ing for lung cancer.38 This conclusion is based on the fact that the National Lung Screening Trial was performed at major centers with strict protocols (not community hospitals) and 40% of patients required some type of follow-up study or intervention because of positive results, and that the long-term hazards from cumulative radiation exposure with this screening are unknown. In light of differing guidelines, an approach of shared decision making and educating patients on the potential benefits and risks in relation to their personal health and health care setting is essential.

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SORT: KEY RECOMMENTATIONS FOR PRACTICE

Evidence

Clinical recommendation rating References

Chest radiography should be performed in patients with signs and symptoms consistent with lung cancer, C 17, 19, 22

and contrast-enhanced computed tomography should be performed if a likely alternative diagnosis is not

identified on the chest radiograph.

The diagnosis of suspected lung cancer should be confirmed using the least invasive method possible. C 22

Endobronchial ultrasound and electromagnetic navigation can increase the diagnostic yield of bronchoscopy C 23, 24

for mediastinal or peripheral lesions.

Medically fit patients with infiltrative stage III non–small cell lung cancer should be offered chemotherapy A 31

and radiation therapy.

Patients with stage III non–small cell lung cancer should receive chemotherapy and radiation therapy. A 32

Early limited stage small cell lung cancer is treated with chemotherapy and radiation therapy, and possibly C 34

surgery in the earliest stages.

Early palliative care results in improved quality of life and a decreased incidence of depression in patients with B 33

newly diagnosed non–small cell lung cancer.

Consider screening high-risk patients for lung cancer annually with low-dose computed tomography (number A 35, 36

needed to screen of 312 to prevent one death).

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Prevention

Never smoking is the best way to prevent lung cancer, and smoking cessation is helpful. The USPSTF recommends screening every patient for tobacco use and encouraging smoking cessation for smokers at every appointment.39 Physician counseling techniques can be effective when tailored to a patient’s willingness to change.40 A variety of pharmacologic modalities are available that work best when combined with social and behavioral support. Leg-islation such as smoking bans in public buildings, pro-hibiting marketing of tobacco products to minors, and taxation of tobacco products likely play a role in decreas-ing tobacco use.41

Physician and Patient Resources

The National Cancer Institute website (http://www. cancer.gov/cancertopics/pdq/adulttreatment) is a helpful resource for physicians and patients. Clinical practice guidelines are summarized on the National

BEST PRACTICES IN PREVENTIVE MEDICINE: RECOMMENDATIONS FROM THE CHOOSING WISELY CAMPAIGN

Recommendation Sponsoring organization

Do not perform computed American College of Chest

tomography screening for Physicians/American

lung cancer among patients Thoracic Society

at low risk of lung cancer.

SOURCE: For more information on the Choosing Wisely Campaign, see http://www.choosingwisely.org. For supporting citations and to search Choosing Wisely recommendations relevant to primary care, see http://www.aafp.org/afp/recommendations/search.htm.

Comprehensive Cancer Network website (http://www.

nccn.org/professionals/physician_gls/f_guidelines.

asp#site; free registration required).

Data Sources: We searched PubMed, Clinical Inquiries, the Cochrane database, the USPSTF, and Ovid. In addition, we relied heavily on the ACCP 2013 lung cancer evidence-based guidelines. We used references from recent review articles from UptoDate and American Family Physi-cian. We limited our search timeline to the previous five years. Search dates: January through March 2014.

The views expressed are the authors’ and do not reflect the official policy or position of the U.S. government, Department of the Navy, or Depart-ment of Defense.

The Authors

KELLY M. LATIMER, MD, MPH, FAAFP, is program director of the Family Medicine Residency Program at Naval Hospital Pensacola (Fla.) and is an assistant professor at the Uniformed Services University of the Health Sci-ences in Bethesda, Md.

TIMOTHY F. MOTT, MD, is a staff physician in the Department of Family Medicine at Naval Hospital Pensacola and is an assistant professor at the Uniformed Services University of the Health Sciences.

Address correspondence to Kelly M. Latimer, MD, MPH, Naval Hospital Pensacola, 6000 West Highway 98, Pensacola, FL 32512. Reprints are not available from the authors.

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256 American Family Physician www.aafp.org/afp Volume 91, Number 4 ◆ February 15, 2015

Lung Cancer

eTable A. Histologic Classification of Lung Cancer

Percentage

of all lung

Type cancers Classic presentation

Non–small cell lung cancer 80

Adenocarcinoma (lepidic, acinar, 40 Peripheral

papillary, micropapillary,

fetal, colloid, mucinous)

Squamous cell carcinoma 25 Central, associated more

with smoking

Large cell carcinoma 10 Peripheral

Small cell lung cancer (small cell, 15 Central, massive

combined small cell) lymphadenopathy,

paraneoplastic syndromes

Other uncommon types (such as 5 Varies

carcinoid)

Information from: Neiderhuber JE, Armitage JO, Doroshow JA, Kastan MB, Tepper

JE, eds. Cancer of the lung: non–small cell lung cancer and small cell lung cancer. In:

Abeloff’s Clinical Oncology. 5th ed. Philadelphia, Pa.: Saunders; 2013.

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