What every physician needs to know:

Lung cancer remains a leading cause of mortality in the United States. Despite advances in screening and early detection, the majority of patients still present with advanced disease. Despite the recent therapeutic discoveries in targeted treatment, and immunotherapy, cures are rare and the major objective of therapy is palliation.


Non-small cell lung cancer is the most common subtype of lung cancer representing roughly 80% of all cases. Non-small cell lung cancer is further subdivided into distinct histologic subtypes including adenocarcinoma, squamous carcinoma, large cell, and pleomorphic carcinomas. Large cell neuroendocrine remains classified as a non-small cell cancer. It has become important that the histologic subtype is carefully identified since treatment options may vary depending on type of cancer. The majority of recent therapeutic discoveries have been in adenocarcinoma.

At diagnosis several diagnostic tests and procedures can be done to accurately stage the disease. Staging is crucial for the determination of therapy and prognosis.

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Please refer to chapter on lung cancer staging.

Are you sure your patient has non-small cell lung cancer? What should you expect to find?

Lung cancer presentations may vary depending on the extent of disease. Increasingly with the prevalence of CT scans, small nodules maybe found incidentally in asymptomatic patients. However, the majority of patients present with one or more symptoms.

  • Symptoms from local disease:

This includes cough, hemoptysis, chest pain and dyspnea. These symptoms are often non-specific and may be present for some time prior to a formal diagnosis. Patients are frequently treated with 1 or multiple courses of antibiotics for “pneumonia” prior to imaging or referral for diagnosis.

2. Symptoms from distant disease:

Symptoms depend on the location of the distant spread, e.g., bone metastasis may cause pain while brain metastases may cause neurologic compromise. Adrenal and liver involvement is often asymptomatic.

3. Symptoms related to paraneoplastic syndromes:

Paraneoplastic syndromes vary widely and may be associated with specific histologic cell type. The most common paraneoplastic syndromes include: anemia, weight loss, SIADH, hypercalcemia, hypertrophic osteoarthropathy and neuropathies. Refer to chapter on paraneoplastic syndromes.

Beware: there are other diseases that can mimic non-small cell lung cancer:

Infection or inflammation can sometimes mimic lung cancer. A diagnosis of granulomatous diseases such as Mycobacterial infection or Sarcoidosis may also present with mediastinal adenopathy and/or lung nodules. Tissue diagnosis is often required to confirm the diagnosis and direct further treatment.

How and/or why did the patient develop non-small cell lung cancer?

The most important risk factor for lung cancer is tobacco exposure, particularly cigarette smoke. Other risk factors are less common and include exposure to toxins such as asbestos, radon and external beam radiation. Family and personal history of malignancy also increase the risk. Second hand smoke exposure elevates the risk above baseline, however, the risk is significantly less than that of a personal history of cigarette smoke.

The sharpest increase in incidence, however, is in never smokers who represent a distinct subtype of the disease. These patients often have a different biology and different susceptibility to treatment.

There does appear to be a gender difference and premenopausal women do appear to be at a slightly lower risk.

Which individuals are of greatest risk of developing non-small cell lung cancer?

The patients at the highest risk for developing lung cancers are those with multiple risk factors. Current smokers or smokers having quit recently are at the highest risk. There is also a dose response in that those with a greater exposure (more cigarettes per day for a longer time) are at higher risk. In the past several years, COPD was identified as an independent risk factor for the development of lung cancer beyond that of the tobacco exposure. Patients with a personal or family history of lung cancer, particularly if they developed their cancer at an earlier age and/or with less tobacco exposure do have a higher likelihood of developing a lung cancer. As stated above, there is a gender difference with males being more susceptible and having a worse prognosis than females. In addition, age is a risk factor for the development of lung cancer.

This said, there is an increasing incidence of lung cancer in never smokers.

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

Although there is much interest in the development of biomarkers for lung cancer, a reliable laboratory study to establish diagnosis has yet to be developed. Common serum tumor markers such as CEA are unreliable at best.

Routine blood work to identify paraneoplastic syndromes or metastatic involvement can be performed in the appropriate clinical context. A baseline CBC and metabolic panel may be useful to identify anemia; elevated calcium and LDH for bony involvement or hypercalcemia related to PTH-like peptide and serum sodium for SIADH.

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

The diagnosis is often suspected based on imaging initiated after symptoms are reported. Incidental findings identified on CT scans performed for other reasons are not uncommon. In the era of CT screening of high-risk patients for lung cancer, there is an ever increasing number of screen identified lung cancers.

PET and CT-PET scans are approved for the initial staging of lung cancer. The metabolic activity in the tumor may herald the indolence or aggressiveness of the tumor. Also, the radiographic appearance on CT may suggest the potential for more or less aggressive tumor behavior. Pure ground glass lesions tend to be more indolent while solid and sub-solid lesions are often more rapidly evolving. PET can be quite useful to help guide the site for tissue sampling. It may identify occult metastatic involvement, which should be sampled to both diagnose and stage the patient with the same procedure. In the past, bone scan was recommended to elucidate bony involvement, however, PET is very sensitive for bone metastases rendering bone scan obsolete in most cases.

MRI of the brain is also approved for initial staging of lung cancer. It is more sensitive than CT of the brain. Most patients are able to tolerate MRI brain, however, in the few with severe claustrophobia, CT brain with and without contrast may be considered.

Ventilation and perfusion scan can be considered in those patients being considered for resection and who have concerns regarding their ability to tolerate surgery. Those with borderline pulmonary reserve may benefit from a perfusion scan to help inform the post-operative predicted lung function.

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

Pulmonary function testing is performed in most patients, however, it does not inform the diagnosis but rather help elucidate the patient’s tolerance for resection or subsequent lung destruction from toxicity.

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

The available diagnostic procedures for lung cancer include percutaneous biopsy, bronchoscopy with or without guidance (electromagnetic navigation, endobronchial ultrasound, etc) or surgical biopsy. When considering the most appropriate diagnostic test, it is important to biopsy the highest stage lesion and to obtain sufficient tissue to help guide treatment.

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

The diagnosis is made on careful examination of tissue histology. Immunostains will help confirm the tumor primary is indeed lung. Stains for TTF-1 and mucin or p40 and p63 are consistent with adenocarcinoma and squamous cell lung primaries respectively.

Molecular testing for targetable mutations should be considered in the appropriate patient. Typically patients with adenocarcinoma with a minimal or never smoking history. Patients who have squamous carcinomas and have never smoked should also be screened for presence of targetable mutations.

Molecular testing usually refers to a mixture of Next Generation Sequencing (NGS-tumor DNA sequencing to look for actionable mutations) in addition to in situ hybridization (FISH). These tests continue to evolve as discovery of new targets improves.

Targetable mutations include EGFR, ALK, Ros, RET, as well as BRAF and Her2.

It should be noted that NGS may take up to 3 weeks or longer for results and in some sites, EGFR and ALK immunohistochemistry can provide a rapid if not 100% accurate estimate for the presence of these 2 targets.

In addition, testing for Programmed Death-Ligand 1 expression (PD-L1) is important for immunotherapy treatment.

While NGS and PD-L1 measurement is routine in advanced stage disease, for early stage non-small cell lung cancer the role of testing is less defined.

If you decide the patient has non-small cell lung cancer, how should the patient be managed?

Treatment options based on the stage at diagnosis:

For stage Ia or Ib non-small cell cancer patients surgery alone is the main modality of therapy. Sub-group analysis of adjuvant chemotherapy has demonstrated no benefit for the majority of patients in this population and the potential for increased harm. Select patients with stage IB disease may be considered for adjuvant chemotherapy, in particular those with tumors exceeding 5 cm and those with high-risk features. The decision regarding the most appropriate surgical approach depends on local expertise and availability.

In patients with early stage disease but who are poor surgery candidates, local treatment options should be considered. These include sub-lobar resection, thermal ablation and stereotactic radiotherapy (SBRT). Multiple modalities exist to perform ablation including cryoablation, radiofrequency ablation, photodynamic therapy and microwave. The majority of these procedures are performed percutaneously by interventional radiology, however, endoscopic approaches are evolving.

Stage II non-small cell cancer patients should be treated with surgery followed by adjuvant chemotherapy or alternatively neo-adjuvant chemotherapy followed by surgery if candidates. Patients not deemed surgical candidates may be offered concurrent chemotherapy and radiation. Standard chemotherapy for these patients is cisplatin.

Patients with stage IIIA non-small cell lung cancer may be offered one of 3 choices: 1) neo-adjuvant chemotherapy followed by surgery and then radiation; 2) definitive concurrent chemotherapy and radiation; or 3) neo-adjuvant concurrent chemotherapy and radiation followed by surgery. Treatment preference varies by institution particularly with respect to whether to consider resection after concurrent chemotherapy and radiation. The most common approach is likely definitive concurrent chemotherapy and radiation.

Stage IIIB is treated with concurrent chemotherapy and radiation, although in the setting of extensive disease chemotherapy alone may be used as the prognosis for these cases is similar to stage IV.

Stage IV disease treatment depends on results of histopathology, Next Generation Sequencing (NGS) and PD-L1 testing. If a patient has a targetable mutation then a targeted agent is preferred first line therapy.

Twenty percent of patients with adenocarcinoma are found to have EGFR (Epidermal Growth Factor Receptor) mutant disease and may be considered for a Tyrosine Kinase Inhibitor (TKI). Currently available first line TKIs include Erlotinib and Gefitinib. Over time patients may develop resistance to the TKI. Exon 20 insertion and more commonly T790M acquired mutations confer resistance to TKI and therefore re-biopsy should be performed to determine candidacy for 3rd line agents.

Checkpoint inhibition represents a pathway to amplify the immune response to tumor cells. CTLA-4 (Cytotoxic T lymphocyte antigen-4), PD1 (Programmed Death 1 receptor), and PDL-1 (Programmed Death 1 ligand) are all pathways of “immune tolerance” to tumor cells that currently have commercially available agents, referred to as immunotherapy.

In patients with high expression of PD-L1 and negative NGS immunotherapy is preferred. However, those who are negative for NGS and PD-L1 are considered candidates for chemotherapy. That said, there is a recent approval for combined chemotherapy plus immunotherapy in untreated patients regardless of PD-L1 expression. All patients despite clinical stage should be considered for clinical trial if one is available as the landscape for treatment of lung cancer is rapidly evolving.

The toxicities, in particular pulmonary, of the various treatment modalities can be significant and should be thoroughly discussed with the patient. Several targeted therapies and immunotherapy can cause interstitial pneumonitis. It is important to recognize the symptoms and signs early so as to allow for early intervention.

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

Prognosis depends on the stage at presentation with higher stage portending a worse prognosis. Stages I and II as well as IIIA are potentially curable, while IIIB and IV are felt to be mostly palliative. This said, the impact of newer therapeutics including immunotherapy on prognosis is yet to be seen.

What other considerations exist for patients with non-small cell lung cancer?

It is important that patients diagnosed with lung cancer, especially advanced stage, be offered the services of a palliative care program for symptom management from both the disease itself as well as the treatment. Early intervention with palliative care has been shown to improve patient outcomes. In addition, patients with advance stage disease can be very debilitated by symptoms from both malignant or paramalignant effusions as well as malignant airway obstruction. Management of refractory symptoms can have a significant impact on quality of life in these patients (refer to Interventional Pulmonology and Pleural Diseases Chapters).

This article originally appeared on Pulmonology Advisor