Presentation, Diagnosis and Assessment

Clinical Presentation

Lung cancer in general, and non-small cell lung cancer (NSCLC) in particular, is often asymptomatic in the early stages of the disease. When symptoms do occur in an early stage (e.g., endobronchial tumors), they include:

• Cough, particularly cough that does not diminish or worsens over time
• Hemoptysis (coughing up blood)
• Dyspnea (shortness of breath)
• Sputum production

In addition to the above respiratory symptoms, advanced-stage NSCLC may present with more severe symptoms, including weight loss, fatigue and other systemic symptoms. The typical sites of metastasis for NSCLC include the brain, bones, liver, adrenal glands and the contralateral lung; metastasis related symptoms, such as pain or other symptoms (e.g., headaches or neurological symptoms for brain metastasis) may also occur. It is important to emphasize that these symptoms are not specific for lung cancer and are often mistaken for other conditions, which can lead to delays in diagnosis. At first diagnosis, the typical patient with lung cancer, including NSCLC, is older (median age 71 years; <10% of cases are in people <55 years old), male (55%), and has a history of tobacco smoking (85-90%). Women with lung cancer are more likely to have been never-smokers than men.

Diagnosis

Establishing a definitive diagnosis of NSCLC requires several critical steps, outlined in Table 2-1. Any symptoms consistent with NSCLC should prompt further investigation.

A full medical history, including comorbidities, weight loss and physical examination, is required. Laboratory tests, including hematological, renal, hepatic and bone biochemistry tests, must also be conducted to assess the patient's overall health status and help select a treatment strategy.

Imaging is crucial for both diagnosis and staging of NSCLC and can be performed utilizing several techniques, each with its own unique advantages and drawbacks. Traditionally, a simple chest X-ray (CXR) was used; however, while a CXR can still be used as the initial step in the diagnostic progress, the false-negative rate is unacceptably high (25%), and thus additional imaging must be utilized in the case of a negative result. A computed tomography (CT) scan provides additional information including the size, number and position of lung tumors; to assess lymph node involvement; and to locate potential extrathoracic metastases (Figure 2-1). As such, a CT scan is a useful modality for cancer staging. Lung cancer is often discovered incidentally on CT scans conducted for other purposes.

Patients without obvious extrathoracic metastasis may benefit from positron emission tomography (PET) scanning. This technique uses a radiolabeled glucose analog, fluorodeoxyglucose (FDG), to identify tissues with high metabolic activity (high glucose uptake), and can be used to risk-stratify the lesions identified on CT, stage mediastinal lymph nodes and identify distant metastases. A combination of FDG-PET and CT provides both anatomical and metabolic information and, thus, both improves diagnostic accuracy and prognostic value, and reduces the number of invasive procedures required for staging. A PET/CT radiograph is shown in Figure 2-2. Nevertheless, even with an FDG-PET/CT scan, false positives (e.g., due to infection, inflammation, or edema) and false negatives (e.g., when lesions are small or with other concurrent lung disease and diabetes) may occur.

While imaging techniques can detect and locate the presence of suspicious lesions that could be cancerous, a definitive diagnosis requires a morphological and histological analysis of putative tumors to determine if they are malignant. Before a biopsy is performed to sample the lesion, risk stratification of nodules identified on imaging should be performed using a validated model, such as the Mayo Clinic Solitary Pulmonary Nodule (SPN) Malignancy Risk Score. The SPN Malignancy Risk Score considers criteria such as age, history of smoking, prior extrathoracic cancer, nodule size, nodule location, and presence of spiculation (irregular, sharp, or jagged edges) on CT imaging. If a FDG-PET scan was performed, the level of FDG uptake can be added to the risk calculation. A score of <5% indicates low risk, that of 5-65% intermediate risk, and that of ≥65% high risk; a biopsy is recommended for intermediate and high risk nodules.

Many biopsy techniques exist that can be employed to obtain putative lung cancer samples. Endobronchial biopsy is a minimally invasive technique performed during bronchoscopy to sample visible tumors or lesions within the trachea or bronchi that can be accessed directly with the bronchoscope. Transbronchial lung biopsy (TBLB) uses a fluoroscopy-guided biopsy forceps, advanced into the peripheral lung via a bronchoscope, to sample lesions which are not directly visible. With TBLB, there is a small (1-5%) risk of complications such as bleeding or pneumothorax. Transbronchial needle aspiration (TBNA) uses a needle, again advanced through a bronchoscope, to penetrate central lung lesions or lymph nodes outside the bronchial wall and aspirate samples for biopsy. This is particularly useful for sampling mediastinal lymph nodes for staging purposes. Radial endobronchial ultrasound (EBUS)-guided biopsy uses a rotating ultrasound probe, passed through a bronchoscope, to locate peripheral lung nodules; once located, the lesion is marked and biopsied using tools like forceps or needles. Bronchial brushing is a method that uses a brush advanced through any working channel to scrape cells from visible lesions on the bronchial mucosa; this method is especially useful for cases where tissue biopsy is not necessary or feasible. Cytological specimens can also be obtained via bronchoalveolar lavage (BAL), which uses sterile saline introduced to a local lung segment through the bronchoscope for this purpose. Electromagnetic navigational bronchoscopy (ENB) uses a virtual 3D model of the patient’s lungs (typically constructed using CT scan data) to guide a biopsy catheter through which biopsy tools can be advanced. Use of ENB is particularly suited for sampling of small, deep-seated lung nodules that are difficult to reach through traditional bronchoscopy but need precise navigation. In image-guided percutaneous fine-needle aspiration (FNA) or core-needle biopsy, a needle is inserted through the chest wall to sample a lung nodule under CT or ultrasound guidance. This method is used to access nodules near the lung surface, pleural-based lesions, or when bronchoscopy is not feasible. Core-needle biopsies are preferred to fine-needle aspirations when a larger amount of tissue is required for diagnosis. When large central airway tumors that require biopsy or debulking are involved, a rigid bronchoscope can be used to provide a wider working channel for biopsy. Other procedures, including EBUS-guided transbronchial needle aspiration, can be done through a rigid bronchoscope as well.

Once the radiographic data and biopsy samples have been obtained, a definitive diagnosis of cancer can be made, and the cancer can be typed. The first task is to distinguish cancerous from benign nodules. Benign nodules, such as granulomas or hamartomas, often have characteristic radiological features, including rounded, smooth, or polygonal contours and distinct calcification patterns (diffuse, central, laminar, or popcorn-like). By contrast, malignant nodules are characterized by features like lobulated or spiculated edges, pleural retraction and an eccentric calcification pattern (or no calcification). Suspicious nodules are definitively tested for malignancy by histological examination of biopsy specimens.

The second task is to type and grade the cancer. As described in Overview the most common types of NSCLC are adenocarcinoma, squamous cell carcinoma (SqCC) and lung carcinoma (LCLC). These can be distinguished from each other and from SCLC based on characteristic morphological features (see Overview) and the presence or absence of histological markers, as assessed by immunohistochemical staining of the biopsy sample:

• Adenocarcinoma is in most cases positive for TTF-1 (the recommended biomarker for this NSCLC type) and Napsin A; note that rarer variants, such as invasive mucinous adenocarcinoma, may show CK7 (or, in rare cases, CK20 or CDX2) expression and be negative for TTF-1.
• Squamous cell carcinoma strongly expresses p40 (the recommended biomarker for this NSCLC type) and p63, particularly in the keratinizing subtype.
• Large cell lung carcinoma is largely a diagnosis of exclusion, made on the basis of morphological characteristics and a lack of markers for adenocarcinoma or SqCC; a diagnosis of LCLC should be reserved for specimens obtained after resection.
• Small cell lung carcinoma commonly expresses neuroendocrine markers, including Chromogranin A, Synaptophysin, and NCAM/CD56 (the most sensitive but least specific marker); note that SCLC is often positive for TTF-1, and it is the presence of neuroendocrine markers that is key.

In addition to providing the material to confirm the diagnosis and determine the histological type of the cancer, biopsies can also help in staging the cancer by determining whether the cancer has spread to the lymph nodes or other tissues. In addition, the material provided by the biopsy can be tested for the presence of biomarkers that can guide the choice of therapy.

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