What every physician needs to know:

Worldwide, lung cancer is the leading contributor to new cancer cases, with over a million new cases or about 13 percent of all new cancer cases. Lung cancer is also the leading cause of cancer-related deaths worldwide, with over 900,000 deaths or about 18 percent of all cancer-related deaths. In the United States estimates more than 225,000 new cases of lung cancer in 2011 and almost 200,000 cancer-related deaths. Lung cancer accounts for 31 percent of cancer deaths in men and 25 percent of cancer deaths in women. The overall five-year survival for all patients diagnosed with lung cancer is 12-14 percent. Deaths from lung cancer exceed those from colon, breast, and prostate cancer combined.

Of all patients diagnosed with lung cancer, about half present with distant metastatic disease, 25 percent present with locally advanced disease, and the last 25 percent present with localized disease. This last group is best treated with surgical resection as the primary therapy. Locally advanced tumors may also benefit from surgery but only following preoperative (neo-adjuvant) chemo/radiation therapy in selected patients.

Surgery for lung cancer

Surgery for lung cancer consists of two types of procedures: staging and curative. Staging procedures consist of cervical mediastinoscopy, anterior mediastinotomy (Chamberlain procedure), needle techniques (i.e., endobronchial ultrasound [EBUS] and endoscopic ultrasound [EUS]), and VATS (video-assisted thoracic surgery) with biopsy. Curative procedures are sublobar resection, lobectomy, bi-lobectomy, and pneumonectomy. Surgery can be performed using either open thoracotomy or minimally invasive techniques (i.e., VATS or robotics).

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From a pathology standpoint, lung cancer is divided into two general types: small-cell lung cancer and non-small-cell lung cancer. Non-small-cell cancers make up about 85 percent of cancers seen in clinical practice, while the other 15 percent are small-cell cancers.

The non-small-cell tumors are squamous cell carcinomas, adenocarcinomas (e.g., fetal variants and ground glass nodules [GGOs]), undifferentiated large-cell carcinomas, adenosquamous carcinomas, and basaloid carcinomas. GGOs begin as atypical adenomatous hyperplasia (AAH) and progress through carcinoma in situ (CIS) and then minimally invasive adenocarcinoma (MIS). Note that the term “bronchoalveolar carcinoma” is no longer routinely used. Small-cell carcinomas are included in the neuroendocrine tumors of the lung, which also include large-cell neuroendocrine carcinoma, atypical carcinoid, and typical carcinoid tumors.

From a staging standpoint, lung cancer is divided into four stages, I-IV, based on the size, location and extent of invasion of the tumor; the presence or absence of lymph node metastases; and the presence and location of metastatic disease, as outlined by the most recent revision of the TNM staging system by the International Association for the Study of Lung Cancer (IASLC). As for all cancers, there are four important reasons to accurately stage all lung cancers:

  • To allow precise communication among caregivers

  • To predict overall outcome/survival

  • To devise treatment

  • For research purposes

Knowing the precise stage of a lung cancer is imperative when considering treatment, as surgical therapy is usually reserved for stage I and II patients and carefully selected stage III patients.

Are you sure your patient has lung cancer? What should you expect to find?

Lung cancer detection, whether by screening or clinical presentation, is most accurate when there is a high clinical suspicion in the appropriate setting. Early lung cancer is rarely symptomatic, and early symptoms of lung cancer frequently mimic other more common ailments (e.g., chronic cough, shortness of breath, chest pain). More than 90 percent of lung cancer patients ultimately develop symptoms during the course of their disease.

One third have local symptoms that are bronchopulmonary (cough, shortness of breath, wheezing, hemoptysis) and/or non-bronchopulmonary (pain, dysphagia, SVC syndrome). One third have symptoms of metastatic disease (bone pain, jaundice, adrenal insufficiency, pathologic fractures, neurological deficits), and a third have non-specific symptoms (weight loss, paraneoplastic syndromes). Patients can have a combination of these symptoms as well.

Many patients present with a lung nodule found during a work-up or evaluation for another medical problem or on chest x-rays performed during routine physical examination. The proper follow-up and approach to treatment of a new lung nodule have been extensively studied, and the accepted protocols are beyond the scope of this text. However, any patient with a history of cigarette smoking, COPD, or asbestos exposure, or a family history of lung cancer who is found to have a lung nodule should be closely followed with serial imaging scans or worked up and considered for surgical excision, depending on the level of clinical suspicion. The same protocol applies for larger nodules (>1 cm) and nodules in the upper lobes (R>L).

Beware: there are other diseases that can mimic lung cancer:

Many non-malignant and malignant diseases can present in a manner that is indistinguishable from that of lung cancer (i.e., solitary pulmonary nodule [SPN] or lung mass). There is no universally accepted definition of a solitary pulmonary nodule, but Gould and associates defined a solitary pulmonary nodule as a single, spherical, well-circumscribed, radiographic opacity that measures not more than 3 cm in maximal diameter and that is surrounded completely by aerated lung. In a solitary pulmonary nodule, there is no associated atelectases, hilar enlargement, or pleural effusion.

Any solid finding in the lung that is larger than 3 cm is technically considered a lung mass, while any nodule that lacks clear-cut radiographic characteristics that define it as either malignant or benign is considered indeterminate. Indeterminate nodules can only be further defined as either benign or malignant by review of old films or follow-up radiologic evaluations.

Historically, the rates of malignancy for SPNs are between 30 and 50 percent. One model developed to predict “pretest” probability of malignancy showed that six independent factors helped to predict malignancy: older age, current or past smoking, a history of extrathoracic cancer at least five years before nodule detection, nodule diameter (any lung nodule >3 cm in diameter will be malignant in >90% of cases), spiculation, and upper lobe location. One rule of thumb used by many practitioners is that for a new nodule in a patient with a significant smoking history, the chance that the nodule represents a cancer is approximately equal to the patient’s age.

Lung cancers make up the majority of malignant SPNs (85-95%), and granulomas constitute a similar proportion of the benign nodules. Metastatic disease (the next most common malignant source of SPNs, at 10-15%) usually presents with multiple, randomly distributed, peripheral, non-spiculated nodules, but it can present as an SPN as well. Of the benign tumors that present as SPNs, hamartomas are the most common, accounting for about 5 percent of all SPNs. Most granulomas are the residua of prior infections, such as Histoplasma capsulatum, Coccidioides immitis, and Mycobacterium tuberculosis, but they can also be due to non-infectious etiologies, such as sarcoidosis.

A thorough history, physical exam, and review of any prior radiographs goes a long way toward classifying the probability of malignancy into low (<5%), intermediate (5-60%), or high groups (>60%). These patients can then be worked up, followed, and treated according to evidence-based protocols.

How and/or why did the patient develop lung cancer?

Lung cancer is the most common cancer and the most common cause of cancer mortality in the United States and worldwide. The estimated numbers of lung cancer cases worldwide has increased by 51 percent since 1985, with those in men up 44 percent and those in women up 76 percent. Almost half (49.9%) of lung cancers occur in developing countries, which is down significantly from 69 percent in 1980. While lung cancer incidence and mortality are highest in the United States and in the developed countries of Europe, the rates in developing geographic areas, including Central America and most of Africa, are low. It is estimated that lung cancer deaths will continue to rise worldwide because of increasing global tobacco use, especially in China and India.

The overall five-year survival rate for lung cancer in the United States is about 15 percent, though the five-year survival rate globally is worse; the five-year survival rate in Europe, China, and developing countries is estimated at 8.9 percent. Therefore it is becoming clear that prevention should be a major focus in the field of lung cancer treatment, with increased understanding of the disease’s epidemiology and risk modification used to reduce the occurrence of the disease.

Tobacco smoking

Cigarette smoking was modest prior to World War I. In 1900, the annual adult consumption was less than 100 cigarettes, whereas this number rose to more than 3,500 in 1950 and peaked at more than 4,400 in the mid 1960s.

At the turn of the twentieth century, lung cancer was uncommon. In 1912, Adler reported an extensive review of autopsy reports from US and western European hospitals and found 374 cases of primary lung cancer, or less than 0.5 percent of all cancer cases. Over the next few decades, several reports of lung cancer noted the increasing incidence of the disease relative to that of other cancers. As early as 1930, Roffo concluded from observations of patients and animal studies that tobacco tar that was liberated from the burning of tobacco was a carcinogen. Over the next twenty years, multiple reports in the medical literature called attention to the potential relationship of cigarette smoking and lung cancer.

In 1950, two landmark epidemiologic studies that examined the causal relationship of tobacco smoke and lung cancer were published. Wynder and Graham reported on a case control study that examined 605 cases of lung cancer in men with the general male population that was free of cancer, drawing three conclusions:

  • Excessive and prolonged tobacco use is an important factor in the induction of lung cancer.

  • The occurrence of lung cancer in the non-smoker is rare.

  • A lag period of ten years or more between the cessation of smoking and the occurrence of lung cancer is common.

The second study was a similar case control study from the United Kingdom. Doll and Hill interviewed 649 male and 60 female lung cancer subjects and compared them to 1,700 patients without lung cancer. The authors concluded that there was a causal relationship between tobacco smoking and lung cancer and that the effect on the development of lung cancer varied with the amount of cigarette use.

Pisani and colleagues estimated that 20 percent of all cancer deaths worldwide could be prevented by the elimination of tobacco smoking. Clearly, tobacco smoking is the most important modifiable risk factor for lung cancer.

Genetic factors

Over the past twenty years, a plethora of data has been accumulated on the genetics of cancer, and lung cancer is no exception. Two Japanese studies showed an association between lung cancer and rare cancer syndromes like Bloom’s syndrome and Werner’s syndrome. A recent meta-analysis showed that the risk of lung cancer in people with a positive family history of lung cancer is twice that of those with no such family history. This increased risk remains even among non-smokers.

Many studies have examined genes and gene sites that may determine candidate susceptibility, mostly as they relate to the absorption and metabolism of tobacco or other carcinogens in lung tissue. Studies have also shown that there is a genetic variability in the process of DNA repair following the inflammation that occurs during exposure to tobacco smoke. Other factors, such as mutagen susceptibility, acquired or epigenetic changes to DNA, and a number of cell cycle genes, have all been implicated in lung cancer risk.


Several nonmalignant lung diseases have been associated with an increased risk of lung cancer. Chief among these is chronic obstructive pulmonary disease (COPD). Although smoking causes both COPD and lung cancer, several studies have shown that airflow obstruction is an independent risk for the development of lung cancer. Several diseases that lead to interstitial fibrosis have also been implicated with an increased risk of lung cancer.

Hubbard and colleagues evaluated 890 patients with idiopathic pulmonary fibrosis (IPF), compared them to 5,884 controls, and found that the patients with IPF had a significantly higher incidence of lung cancer than did the controls (1:8.25), even after adjusting for smoking. Other diseases that produce fibrosis (e.g., scleroderma) have also been shown to increase the risk of lung cancer.


Since 1950, there has been a 600 percent increase in lung cancer mortality in women. Some of this increase can be attributed to the increasing prevalence of cigarette smoking among women since WWII, but several studies have questioned whether women are also more susceptible to the carcinogenic effects of tobacco than are men. In a case-control study from Ontario, Canada, Risch and associates showed that the odds that a woman with a history of forty pack-years of cigarette smoking would develop lung cancer were 1:27.9 compared to 1:9.6 in men.

Similarly, Zang and Wynder showed that the dose-response odds ratio for the development of lung cancer in women was between 2.2 and 2.7 times higher in women than in men.

In both studies, the increase in lung cancer risk held for all histologic types of cancer. This difference in susceptibility may be related to a number of factors, such as sex-related differences in nicotine metabolism and metabolic activation or detoxification of lung carcinogens. Several studies have also shown that lung cancers occur more commonly in nonsmoking women than in nonsmoking men. In the study by Zang and Wynder, the proportion of lung cancer patients who had never smoked was more than twice as high for women as for men.

Race and ethnicity

Although race and ethnicity are complex issues in terms of the risk of disease, several studies have shown increased risk of lung cancer for certain ethnic groups. Menck and colleagues showed a substantial increased risk of lung cancer in African Americans, native Hawaiians, and other Polynesians and a lower risk among Japanese Americans and Hispanics, when compared to Caucasians in the United States. These findings held even after smoking habits were taken into account. In addition, Cote and colleagues showed that first-degree relatives of African American patients with early-onset lung cancer were at greater risk of developing lung cancer than were their Caucasian counterparts. The lung cancer survival rate among African Americans was 14 percent lower than that in Caucasians during 1995 to 2000.

Occupational exposure

Asbestos has historically been the most widely appreciated and most common occupational cause of lung cancer. Asbestos is a naturally occurring fibrous mineral that consists primarily of two groups of fibers: serpentine and amphibole. Used commercially since the late 1800s, asbestos’ fire-retardant qualities and strength made it useful in construction and insulating materials. However, it is now widely recognized that asbestos exposure can lead to several pleural and pulmonary manifestations.

The distinction between asbestos exposure and asbestosis becomes very important, as there is controversy as to which leads to an increased risk of lung cancer. In an extensive literature review, Egilamn and Reinert concluded that asbestos meets the accepted criteria for causation of lung cancer in the absence of clinical or parenchymal asbestosis, so asbestos exposure can act as a carcinogen independent of the presence of fibrosis that is due to asbestosis.

Other epidemiologic studies have called into question the carcinogenesis of asbestos fibers in the absence of fibrosis, but it is accepted that the risk of developing lung cancer from nonoccupational exposure to asbestos in the general environment is extremely low. Moreover, the chrysotile fibers are much less carcinogenic than the amphibole fibers are, and in the US chrysotile fibers are by far the more commonly used.

Finally, cigarette smoking clearly potentiates the risk of lung cancer in those with asbestos exposure, although the magnitude of this added effect is unclear. Hammond and colleagues estimated that the combined effect may be anywhere from fifteen to fifty times that of smokers without occupational asbestos exposure.

Mining is the oldest identified occupation associated with lung cancer. In the late nineteenth century, autopsies performed on miners revealed that the “wasting disease” frequently seen in this population was due to lung cancer. These same mines produced the material that Marie Curie later used to isolate radium. Radon (radon-222) is a naturally occurring decay product of radium-226, which is itself a decay product of uranium-238.

Both uranium and radon are naturally occurring isotopes found in soil and rock. At normal temperatures, radon is released as an inert radioactive gas as a decay product of radium. Other decay products of radon produce alpha radiation, which can produce damage to lung cells and genetic material when inhaled. The concentration of radon is highest in poorly ventilated underground mines. The risk of lung cancer related to radon depends on both the cumulative dose and the rate of exposure to the gas. The risk reaches its maximum about ten years after exposure and declines afterward. Smoking potentiates the risk of lung cancer development with radon exposure, and non-occupational exposure produces a very low overall risk for lung cancer.

Which individuals are at greatest risk of developing lung cancer?

Those who smoke are at greatest risk for lung cancer.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

While there are no specific laboratory studies that will either rule in or rule out cancer of the lung, in some patients where the suspicion exists, some abnormal laboratory values will suggest the diagnosis and/or complications of the diagnosis. The most intriguing of these laboratory abnormalities occurs with the paraneoplastic syndromes associated with this disease. While it is not unusual to have elevated levels of antidiuretic hormone (ADH) or parathyroid hormone (PTH) in patients with lung cancer, only 2 percent of lung cancer patients develop a frank paraneoplastic syndrome.

Paraneoplastic syndromes can occur in clinically occult tumors, and they are not dependent on tumor size or stage. In addition, effective treatment of the tumor usually results in resolution of the syndrome. A few of the more common paraneoplastic syndromes associated with cancer of the lung are discussed below.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

SIADH causes hyponatremia and can lead to nausea, seizures, altered mental status, lethargy, and coma. This paraneoplastic syndrome is more common in small-cell carcinoma than in non-small-cell carcinoma and is more common in women than in men. Diagnosis is made by demonstrating hyponatremia in the setting of high urinary sodium excretion. Acute treatment is with fluid restriction and demeclocycline to block the action of ADH at the renal tubules. This syndrome usually responds well to treatment of the tumor, but it frequently returns with tumor recurrence. SIADH can also be due to brain metastases, which should be ruled out with brain imaging.


Hypercalcemia, which is primarily induced hormonally as bony destruction from metastases, is generally not sufficient to cause clinical hypercalcemia. Serum levels of tumor-produced PTH (PTHrp) correlate well with calcium levels. Symptoms include nausea, constipation, anorexia, polydipsia, polyuria, irritability, and altered mental status. Signs include hyporeflexiaand cardiac arrhythmias. Squamous cell cancers are most frequently responsible for hypercalcemia, and treatment of the tumor usually results in rapid improvement.

Cushing's syndrome

Tumor production of adrenocorticotropic hormone (ACTH) occurs primarily in small-cell cancer. Because the ACTH levels rise rapidly, the classic manifestations of the syndrome do not have time to develop prior to clinical presentation. Instead, these patients present with edema, muscle weakness, hypokalemia, metabolic alkalosis, hyperglycemia, elevated cortisol levels, and elevated ACTH levels. Because the tumors secrete the ACTH autonomously, ACTH and cortisol levels are not suppressed by steroid administration. Treatment of the tumor results in rapid improvement.

Anemia and hematologic abnormalities

Multiple hematologic abnormalities are associated with lung cancer, and two of the most common are thrombocytosis and normochromic normocytic anemia. Anemia in these patients is frequently due to decreased iron intake, shortened red cell survival time, and decreased serum iron and iron-binding capacity. Other possible hematologic findings include thrombocytopenia, sideroblastic anemia, hemolytic anemia, red cell aplasia, erythrocytosis, eosinophilia, idiopathic thrombocytopenic purpura, and disseminated intravascular coagulation.

What imaging studies will be helpful in making or excluding the diagnosis of lung cancer?

Whether a pulmonary nodule is discovered as a result of a screening protocol or incidentally, it should be worked up and treated using the same evidence-based approach. The approach to pulmonary nodules should take into account the number (solitary vs. multiple), size (≤3 cm vs. >3 cm), and morphology, as well as the presence of symptoms and risk factors for malignancy. Several imaging modalities can be used when evaluating patients with pulmonary nodules, each with its own value in the proper context.

Chest x-ray (CXR)

Chest x-ray remains the starting point for the majority of patients found to have a pulmonary nodule, as it is readily available and inexpensive. It is always preferred to obtain both the PA and lateral views, as they provide needed information on the location and character of the nodules. Depending on the location of the nodule, lesions as small as 5mm in diameter can be visualized by plain CXR. However, it is not unusual for larger nodules to be missed by plain CXR, even by experienced chest radiologists. This is especially likely for upper lung lesions, as the bony chest structures tend to hide the nodules. In the Mayo Lung Project, forty-five out of fifty screening-detected peripheral carcinomas were visible on CXR when reviewed retrospectively, and all but one of these tumors were larger than 1 cm.

In all patients with a pulmonary nodule, it is imperative to compare the current CXR with previous films to give the clinician a sense of chronicity and establish whether the nodule has grown or changed in character or has been stable over a period of time. If a nodule can be verified as stable over a two-year period, it can be assumed, with few exceptions, to be benign, with the most notable exception being the ground glass nodule (GGO). Occasionally, a benign diagnosis can be established based on a characteristic pattern of calcification on CXR, as diffuse, central, laminated, and popcorn patterns of calcification are considered benign. If one of these patterns of calcification is seen on CXR, no further investigation is needed.

Chest CT scan

Like CXR, CT scan of the chest is a staple for chest imaging and is readily available in the majority of care centers. It is more sensitive and more specific than CXR for detecting pulmonary nodules, and it provides significantly more information on the size, location, and character of the nodule. The likelihood of nodule detection increases as the slice thickness decreases. As in CXR examination, all previous chest CT scans should be reviewed to compare the nodule’s characteristics over time. CT of the chest can also detect and characterize mediastinal lymphadenopathy, synchronous nodules, and possible invasion of the chest wall or mediastinal structures.

Morphologic characteristics on CT that suggest malignancy include spiculated margins, vascular convergence, dilated bronchus leading to the nodule, and the presence of pseudo-cavitation. True cavitation may also suggest malignancy when it is associated with thick walls. One study found that, whereas only 5 percent of cavities with thin walls (<5 mm) were malignant, more than 85 percent of cavities with thick walls (>15 mm) were cancerous. Like CXR, CT can perceive characteristics that suggest the benign nature of a nodule. For example, a nodule that is less than 2.0 cm with smooth borders and that contains fat density can be confidently diagnosed as a hamartoma.

The risks of CT scan include radiation exposure and adverse reaction to iodinated contrast material. Although the radiation exposure from a single CT scan is low, patients who have multiple follow-up exams should be considered for low-dose studies to minimize radiation risk.

PET/CT scan

FDG-PET/CT scan is a non-invasive functional imaging test that is widely used in clinical oncology for tumor diagnosis, disease staging, and evaluation of treatment response. FDG is selectively taken up by malignant cells that overexpress the glucose transporter protein. In seventeen studies of diagnostic accuracy, PET characterized pulmonary nodules with a high level of sensitivity (80-100%) and variable specificity (40-100%). PET sensitivity drops off significantly when the nodules are less than 8 mm, and the use of PET for characterization of such nodules is discouraged.

There are a significant number of both false positives and false negatives. The classically described false negatives include bronchioalveolar carcinomas, carcinoid tumors, mucinous adenocarcinomas, and tumors in uncontrolled hyperglycemia. False-positive findings are often the result of infectious or inflammatory conditions that include endemic mycoses, tuberculosis, rheumatoid nodules, and sarcoidosis.

Like chest CT scan, FDG-PET/CT scan can be used to characterize pulmonary nodules and mediastinal lymph nodes in patients with high pretest probability (>60%). FDG-PET/CT scan can also be used to characterize uptake in extrathoracic tissues (e.g., intra-abdominal and bony structures). Risk of radiation exposure from PET scanning is low, as the radiation dose is low, but when combined with CT scanning, the radiation dose is somewhat higher.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of lung cancer?

Imaging studies are the most important non-invasive studies to assist in the diagnosis of lung cancer.

What diagnostic procedures will be helpful in making or excluding the diagnosis of lung cancer?

While x-ray studies (plain chest x-ray, CT scan, and PET/CT scan) in the proper clinical setting can suggest malignancy as the diagnosis in a patient with one or more pulmonary nodules, the actual diagnosis requires some form of tissue biopsy for confirmation. There are four commonly used methods for obtaining tissue in patients suspected of having a primary lung cancer.

Sputum cytology

Sputum cytology is the least invasive method of tissue diagnosis in patients with a suspected lung cancer. The accuracy of this method is dependent on rigorous specimen sampling and preservation techniques and on the size and location of the nodule/mass. Patients for whom sputum cytology are most likely to yield a diagnosis are those with bloody sputum, low FEV1, large tumors (>2.4 cm), centrally located tumors, and squamous cell cancers. The sensitivity of sputum cytology in the detection of lung cancer is highly dependent on the number of specimens collected per patient, but overall, the sensitivity is 66 percent, the specificity is 99 percent, the false positive rate is 9 percent, and the false negative rate is 6 percent.

Fiberoptic bronchoscopy (FOB)

Fiberoptic bronchoscopy with or without fine-needle aspiration is a critical step in the work-up of patients who are suspected of having a primary lung cancer, especially patients who present with hemoptysis. With the use of fine-needle aspiration, this procedure can obtain tissue from the primary tumor to confirm or potentially to refute the diagnosis. Tissue diagnosis can be obtained through forceps biopsy, bronchoalveolar lavage (BAL), brushings, and transbronchial needle aspiration.

The size and location of the nodule/mass ultimately determines the overall ability of FOB/TBNA to make the diagnosis. For centrally located lesions that are at least 2 cm in diameter, the overall diagnostic accuracy is 70-100 percent. For peripheral lesions larger than 4cm, the accuracy is 40-80 percent, but it drops to about 30 percent for lesions smaller than 2 cm.

Navigation bronchoscopy

Although this technology does require specialized equipment, computer software, and training, it does allow for bronchoscopic biopsy of small, peripherally located lesions.

Transthoracic needle biopsy (TNB)

Transthoracic needle biopsy has become the diagnostic procedure of choice for peripherally located suspicious nodules. This procedure can be done using either CT guidance or fluoroscopic guidance, although Schreiber and McCrory found that biopsies done with CT guidance had a higher sensitivity than those done under fluoroscopy. For peripheral lesions, TNB has an approximately 90 percent chance of confirming the diagnosis in patients who have lung cancer. However, the false negative rate is 20-30% so a negative needle biopsy (i.e., a non-diagnostic biopsy) cannot be relied upon to rule out cancer.

When a transthoracic needle biopsy provides a specific benign diagnosis, such as tuberculosis, fungal infection, or hamartoma, the chance of “missing” a cancer is very low. In general, patients with a moderate to high likelihood of cancer and who are good surgical candidates do not need preoperative needle biopsy for confirmation, as the biopsy will rarely change the need for surgery, and it can be associated with complications (e.g., bleeding, pneumothorax). Transthoracic needle biopsy is best used for patients who are not surgical candidates and who require tissue confirmation to begin treatment, for patients who are otherwise high operative risks and for whom confirmation would potentially alter treatment, and for patients who insist on having a tissue diagnosis prior to consenting to surgery.

Video-assisted thoracic surgery (VATS)

Video-assisted thoracic surgery offers an alternative to TNB for peripheral nodules that have a moderate to high risk of malignancy. While the major disadvantages are the need for general anesthesia and the need for inpatient resources, VATS has the major advantages of allowing for excisional biopsy and definitive treatment in the same sitting and allowing for pathologic staging using lymph node and other types of biopsies under the same anesthetic.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of lung cancer?

Biopsy or cytologic sampling of a lung lesion is the most direct way of establishing a diagnosis of lung cancer.

If you decide the patient has lung cancer, how should the patient be managed?

Approximately half of patients with non-small cell lung cancer present with metastatic disease. These patients are best treated with systemic therapy (i.e., chemotherapy), which is not discussed here. Of the remaining patients, about half have locally advanced disease and may be candidates for surgical therapy following neo-adjuvant treatment with either chemotherapy or chemo-radiation therapy. The other 25 percent present with truly localized disease and are best treated with surgical resection.

Both invasive and non-invasive methods are available to distinguish between those with and those without mediastinal lymph node involvement. The non-invasive methods of mediastinal staging determine, in the appropriate clinical setting, whether the invasive techniques are needed prior to any attempt at definitive surgical resection.

There are four groups of patients basd on mediastinal status:

  • Mediastinal infiltration: Extracapsular or bulky involvement of mediastinal lymph nodes. These patients do not require invasive staging but simply a tissue diagnosis to begin treatment.

  • Central tumor (medial 1/3 of chest on axial CT image) with hilar lymph node enlargement or abnormal PET uptake: These patients require invasive mediastinal staging prior to surgical treatment.

  • Distinct enlargement or abnormal PET uptake of mediastinal or hilar lymph nodes: These patients require invasive mediastinal staging prior to surgical treatment.

  • Peripheral tumor 3 cm or less with no mediastinal lymph node enlargement or abnormal PET uptake: These patients may not require invasive staging of the mediastinum prior to surgery.

Non-invasive staging

CT Scan:A CT scan of the chest and upper abdomen should be performed for patients with either known or suspected lung cancer who are candidates for treatment. IV contrast is recommended to increase mediastinal lymph node sensitivity. In patients with enlarged discrete mediastinal lymph nodes on CT (>1 cm in diameter) who have no evidence of metastatic disease, invasive mediastinal staging should be performed prior to surgical resection.

PET/CT:All patients with known or suspected lung cancer should undergo PET/CT, where available, to evaluate the mediastinum and extra-thoracic tissues. Patients with an abnormal result in the mediastinum that is suggestive of lymph node involvement should undergo invasive mediastinal staging to rule out such involvement prior to surgical resection.

Patients with a peripheral (the outer two-thirds of the lung) tumor that is less than 3 cm in diameter and who have normal-sized mediastinal lymph nodes that are not hypermetabolic on PET/CT may not need invasive mediastinal staging prior to surgical resection.

Invasive staging

Cervical mediastinoscopy:This procedure, which remains the “gold standard” for invasive mediastinal staging, has stood the test of time for safety and accuracy. Although the procedure is done as an outpatient procedure, it requires general anesthesia because it is performed through a small (<3 cm) incision at the base of the neck in the midline. Pooled sensitivity and specificity values are 78 percent and 100 percent, respectively, with a false negative value of 11 percent. The quoted morbidity and mortality rates are 2 percent and 0.08 percent, respectively. The advent of videoscopic mediastinoscopy has increased the sensitivity to 90 percent and the false negative rate to 7 percent.

Endobronchial ultrasound and fine-needle aspirate (EBUS/FNA):This technique is performed with a specialized fiberoptic bronchoscope equipped with an ultrasonic probe and a port for needle aspiration. The procedure can access many of the same nodal stations as cervical mediastinoscopy, but it is done in the endoscopy suite under light sedation, rather than under general anesthetic. Many studies have found high success rates when mediastinal involvement is present, and this procedure can be repeated on multiple occasions with similar success. However, it requires specialty training and experience to achieve these results. The pooled sensitivity and specificity and false negative rates are 90 percent, 100 percent, and 20 percent, respectively. EBUS/FNA of mediastinal/hilar lymph nodes is now considered to be equivalent to cervical mediastinoscopy in accuracy of mediastinal staging in properly selected patients. It is no longer necessary to confirm a negative EBUS with mediastinoscopy prior to definitive surgery.

Endoscopic ultrasound and fine-needle aspirate (EUS/FNA):This technique is performed using a specialized gastroscope fitted with a curvilinear array ultrasound probe and a port for fine-needle aspiration. EUS can access several lymph node stations–such as inferior pulmonary ligament nodes (station 9), paraesophageal nodes (station 8), aortopulmonary window nodes (station 5), and left adrenal and celiac nodules/masses–that are not commonly available to other techniques. Central vascular invasion (pulmonary artery/aorta) can also be visualized. This technique, which is performed in the endoscopy suite under light sedation, can be combined with EBUS for additional FNA samples (“medical mediastinoscopy”). The pooled sensitivity and specificity and false negative rates have been reported as 83 percent, 97 percent, and 19 percent, respectively.

Video-assisted thoracic surgery (VATS):This technique allows for visual exploration of the pleural cavity with subsequent biopsy of the index lesion or any other potential lesion(s) in the lung or on the pleural, diaphragmatic, or mediastinal surfaces. In addition, several of the mediastinal lymph node stations can be accessed for staging purposes, along with drainage of pleural or pericardial fluid with subsequent cytology examination. The procedure can also be used to rule out the vascular invasion that can preclude definitive resection. VATS, which requires general anesthesia, is associated with a 2 percent morbidity rate, but it can allow for staging and definitive resection at the same sitting. The pooled sensitivity and specificity and false negative rates have been reported as 75 percent, 100 percent, and 7 percent, respectively.

Prior to considering surgical treatment for any patient with a known lung cancer or a highly suspicious lung lesion, the patient should undergo a clinical and physiologic evaluation to determine the perioperative risk. The patient should have a complete history and physical exam by the treating surgeon and should be presented to a multidisciplinary team or tumor board for a full evaluation prior to treatment. There is no data to support the value of denying potential surgical resection based on age alone, and any patient with the appropriate risk factors should undergo preoperative cardiologic evaluation. Surgical resection of lung cancer is best performed by a board certified, specialty trained surgeon on patients whose lobectomy risk does not exceed 4 percent and whose pneumonectomy risk does not exceed 9 percent.

Preoperative work-up

Any patient considered for pulmonary resection of a lung cancer requires an evaluation of pulmonary reserve to help predict the postoperative pulmonary function and, thus, the morbidity and mortality of the proposed procedure. This evaluation begins with the history and physical exam, including questions to ascertain whether the patient has any shortness of breath, how far the patient can you walk prior to becoming short of breath, and how many flights of stairs the patient can ascend prior to stopping because of shortness of breath.

The physical exam should include a thorough exam of the lung fields and observation for signs of longstanding COPD, along with a room air oxygen saturation, where oxygen saturation of less than 90 percent on room air indicates increased risk. Almost all patients who can ascend more than two flights of stairs without shortness of breath can tolerate surgical resection of a lung cancer. Therefore, formal pulmonary function testing (PFTs) has become–and should be–a mainstay in the preoperative evaluation of these patients.

The two most significant values used to assess these patients are the FEV1(forced expiratory volume in one second) and the DLCO (diffusion capacity of the lung for carbon monoxide). If the FEV1 is more than 80 percent predicted for that patient’s body surface area (BSA) and there is no undue dyspnea on exertion or evidence of interstitial lung disease, that patient may safely undergo lung resection, including pneumonectomy. If there is undue dyspnea on exertion, evidence of interstitial lung disease, or the FEV1is less than 80 percent predicted, measurement of the DLCO is recommended.

Measurement of these values allows for a qualitative estimate of the post-operative lung function (i.e., the postoperative FEV1 and DLCO). If the predicted postoperative (ppo) values for these functions is less than 40 percent predicted, a quantitative evaluation of lung function should be obtained with a quantitative perfusion scan, which uses a radioisotope to measure the blood flow to the lungs, including the area to be removed. This measurement allows the exact reduction in function from the proposed surgery to be calculated. If either the ppoFEV1 or the ppoDLCO is less than 40 percent predicted, there is a significant increased risk for perioperative death and cardiopulmonary complication with the proposed lung resection.

Surgical treatment of lung cancer

A review of the expansive literature on the treatment of lung cancer leaves little doubt that, in the appropriate patient population, surgical resection for early-stage tumors is the best treatment and that it provides the best long-term outcomes. More specifically, for patients with clinical stage I or II non-small-cell lung cancer and no medical contraindications to operative intervention, surgical resection is the standard of care. By comparison, patients with clinical stage I or II lung cancer who do not undergo surgical resection (i.e., no treatment) have, on average, a median survival of fourteen months. Chemotherapy and/or radiation therapy improve this survival to twenty-one months (not significant). Both of these survival averages are substantial reductions from the average survival of patients who undergo surgical resection.

Every operation for lung cancer involves three essential steps: establishment or confirmation of the diagnosis and stage, complete resection of the primary tumor, and either systematic sampling or complete dissection of mediastinal lymph nodes.

Establishment/confirmation of diagnosis and stage:A substantial number of patients go to the operating room without a definitive pathologic diagnosis of lung cancer so it is incumbent upon the surgeon to prove the diagnosis prior to performing the resection. Such confirmation is almost always possible using either an excisional or (occasionally) an incisional biopsy of the nodule/mass with immediate frozen section for confirmation. Some tumors are not accessible to these intraoperative biopsy techniques. In patients in whom the nodule is high risk, with preoperative counseling as to the possibility of a benign diagnosis, the definitive resection can be undertaken and serve as both biopsy and treatment.

Knowing the stage of the tumor is essential for both treatment and prognostic purposes, so the surgeon should evaluate the entire pleural cavity both visually and manually prior to definitive resection. If there is any evidence of advanced disease that was not suspected by preoperative staging (e.g., pleural studding with tumor, as occurs in about 6 percent of cases of malignant pleural effusion), these areas should be sampled with frozen-section examination. Any proof of advanced intra-pleural disease should terminate the definitive surgical procedure.

Notable exceptions to this rule include patients with a satellite nodule within the same lobe (T3) or in an adjacent lobe (T4) that is surgically resectable, a nodule with involvement of the chest wall (T3), and a nodule with involvement of a major branch of the pulmonary artery (T4). Unsuspected N2 disease is also best treated by completing the resection and lymph node dissection, followed by adjuvant chemo/radiotherapy.

Complete resection of the primary tumor:Complete resection can be accomplished by any of several procedures based on the tumor size and location, and involvement of adjacent structures. These procedures consist of pneumonectomy, bi-lobectomy, lobectomy, and sub-lobar resection.

The first anatomic surgical resection for lung cancer was a pneumonectomy performed by Evarts Graham in 1933. Over the next ten to twenty years, surgical techniques and advancing medical technology allowed lesser resections (i.e., lobectomy) to be performed that were ultimately proven to be oncologically equivalent and to have significantly less morbidity and mortality. The present expected mortality following lobectomy is 1-3 percent, while that of pneumonectomy is 4-8 percent.

While formal lobectomy remains the “community standard” resection for any stage I or II lung cancer, there is mounting data that even lesser resections (sub-lobar) may provide equivalent oncologic results while preserving pulmonary reserve and reducing morbidity and mortality in properly selected patients. Okada and colleagues analyzed 1,272 consecutive patients who underwent surgical resection for non-small-cell lung cancer and found that lobectomy offered no survival advantage over segmentectomy.

The use of sub-lobar resection has been relegated mainly to patients who do not have the pulmonary reserve to tolerate a formal lobectomy. However, there is mounting evidence that some carefully selected patients who can otherwise tolerate lobectomy can achieve an equivalent oncologic result with sub-lobar resection. These patients are primarily those older than seventy-one years with small (<2 cm) peripheral tumors with ground glass opacity on CT scan. These operations should also include a full lymph node dissection, and the margin of lung resected beyond the tumor should be at least equivalent to the diameter of the tumor (i.e., the margin-to-tumor ratio should be at least 1:1).

The American College of Surgeons Oncology Group (ACSOG) is conducting a phase III trial to determine whether brachytherapy at the time of sub-lobar resection improves local control of tumor compared with sub-lobar resection alone.

Patients with locally advanced tumors (i.e., stages IIIA and IIIB) may also be candidates for surgical therapy following neo-adjuvant chemotherapy and with or without radiotherapy. This treatment remains controversial, as some of the large prospective studies on this topic have failed to show a significant benefit in survival from the addition of surgical resection to neo-adjuvant therapy. This failure was due in part to the high mortality from pneumonectomy (26%) in these trials.

More recent reports have shown a much more reasonable mortality (3-5%) in similar patients who undergo this treatment. There is mounting evidence from retrospective reports that there may be survival benefits in certain groups of Stage III patients who undergo surgical resection. This survival advantage is most closely linked to the clearance of mediastinal nodal involvement (N2 to N0/N1) by the neoadjuvant treatment, so the real question going forward concerns how to determine which patients have this nodal clearance prior to undergoing surgical resection.

Mediastinal lymph node sampling/dissection:It is currently recommended that all patients who undergo a curative resection for lung cancer have an intraoperative systematic mediastinal lymph node dissection or sampling for accurate pathologic staging. This means that the mediastinal lymph nodes from at least three separate lymph node stations should be removed by either of these techniques. While randomized trials have shown superior survival for lymph node dissection compared to sampling, others have failed to show this difference.

It is clear that there is no significant additional morbidity or mortality in lymph node dissection over sampling; both of these techniques are safe, and both provide critical staging information that can influence recommendations regarding postoperative adjuvant therapy and, thus, mortality. At present, there is insufficient evidence to recommend one technique in favor of the other, but all patients who undergo surgical resection of lung cancer should have one or the other.

What is the prognosis for patients managed in the recommended ways?

The prognosis for surgically resected lung cancers varies depending on the study and whether or not the patients have received adjuvant therapy. Overall, the five-year survival rate for patients with stage I lung cancers following complete resection is 75-80 percent for stage IA and 55-60 percent for stage IB. Patients who have complete resection for stage II lung cancers don’t do quite as well; their reported five-year survival rate is 45-50 percent for stage IIA and 30-40 percent for IIB.

The concept of adjuvant chemotherapy for patients with stage I and II lung cancers is developing. The majority of studies published so far have not shown a significant benefit to adjuvant chemotherapy in patients following resection of stage IB tumors. However, the Cancer and Leukemia Group B investigators, which looked at adjuvant chemotherapy for stage IB patients with tumors larger than 4cm, found a statistically significant benefit for these patients. The data for the benefits of adjuvant chemotherapy in stage II patients are very strong. The lung adjuvant cisplatin evaluation meta-analysis found a 27 percent reduction in the risk of death in stage II patients who underwent adjuvant treatment. Therefore, it is current practice to use adjuvant chemotherapy for any patient with stage II or later cancer following surgical resection. Patients with stage IB who have tumors larger than 4 cm should also be included in this group.

What other considerations exist for patients with lung cancer?

Patients with advanced lung cancer benefit from early referral to palliative care services.

What’s the evidence?

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**The original source for this chapter was Drs Brian Berman, Caroline Caperton and Samantha Block. The chapter was revised for this program by Drs Brian Berman, Caroline Caperton and Andrea Maderal.

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