Lung Cancer and more about it

Definition of lung cancer: Cancer that forms in tissues of the lung, usually in the cells lining air passages. The two main types are small cell lung cancer and non-small cell lung cancer. These types are diagnosed based on how the cells look under a microscope.

Lung cancer is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms include cough, chest discomfort or pain, weight loss and less frequently, hemoptysis; nevertheless many patients present with metastatic disease without any clinical symptoms. The diagnosis is normally made by chest X-ray or CT scan and confirmed by biopsy. Depending on the stage of the disease, treatment includes surgery, chemotherapy, radiation therapy or a combination. In spite of advancement in treatment, the prognosis remains poor, with only 15% of patients surviving more than 5 years from time of diagnosis. For patients with stage 4 (metastatic) disease, the 5- year overall survival rate is less than 1%. Survival improvement requires focus on smoking cessation, early detection, and research into the genetic profile of lung tumors and increasing forms of therapy.

Note: In 2009, an estimated 219,440 new cases of lung cancer were diagnosed in the US, and about 159,390 people died from the disease. The incidence of lung cancer has been rising in women but appears to be leveling off in men.

CAUSES OF LUNG CANCER

• Cigarette smoking is the most important and common cause of lung cancer, accounting for about 85% of cases. The risk of cancer varies by age, smoking intensity, and smoking duration; the risk of cancer is lessen after smoking cessation, but it never returns to baseline.

About 15% of people who develop lung cancer have never smoked. In these people, the exact reason lung cancer develops is unknown. Recent studies have reported that some never-smoking people with lung cancer have genetic mutations in the epidermal growth factor gene (EGFR).

• While an environmental association has not clearly been established, it theorized that exposure to radon gas, a breakdown product of naturally occurring radium and uranium, may be an environmental risk factor.
• Other probable risk factors include exposure to secondhand smoke and exposure to carcinogens, such as asbestos, radiation, arsenic, chromates, nickel, chloromethyl ethers, mustard gas, or coke-oven emissions, encountered or breathed in at work.

It is alleged that COPD and pulmonary fibrosis may increase susceptibility to lung cancer. Moreover, active smokers who take beta carotene supplements have an increased risk of developing lung cancer. Air pollution and cigarette smoke contain carcinogens; these substances have not been shown to cause lung cancer, but they may be related with an increased risk. Lastly, people whose lungs are scarred by other lung diseases like Tuberculosis are at an increased risk of lung cancer.

Note: Respiratory epithelial cells necessitate prolonged exposure to cancer-promoting agents and accumulation of multiple genetic mutations before becoming neoplastic (an effect called field carcinogenesis). Eventually, mutations in genes stimulate cell growth which causes abnormalities in growth factor receptor signaling, inhibit apoptosis, and contribute to proliferation of abnormal cells. Also, mutations that inhibit tumor- suppressor genes can lead to cancer.

CLASSIFICATION OF LUNG CANCER

2 major Categories:

• Small cell lung cancer (SCLC)
• Non- small cell lung cancer (NSCLC)

SCLC is significantly aggressive and almost always occurs in smokers.  It is quickly growing, and approximately 60% of patients have common metastatic disease at the time of diagnosis.

The clinical behavior of NSCLC is more inconsistent and depends on histologic type, but about 40% of patients will have metastatic disease outside of the chest at the time of diagnosis. Also, there are variations on other features of the two categories such as the location, risks, treatment and complications.

SIGNS and SYMPTOMS OF LUNG CANCER

Almost 25% of lung cancers are asymptomatic and are detected incidentally with chest imaging. Symptoms and signs can develop from local tumor progression, regional spread, or distant metastases. Paraneoplastic syndromes and constitutional symptoms may occur at any stage of the disease. While symptoms are not specific to the classification or histology of the cancer, certain complications may be more likely with different types.

In Local tumor:

Presenting symptoms are cough, and less frequently dyspnea due to airway obstruction, postobstructive atelectasis, and lymphangitic spread. Also, fever may occur with post obstructive pneumonia. Almost half of patients report unexplained or localized chest pain. Hemoptysis is uncommon, and blood loss is minimal except in some rare instances when the tumor erodes into a major artery, causing massive hemorrhage and death by exsanguinations and asphyxiation.

In Regional spread:

Symptoms are pleuritic chest pain or dyspnea from development of a pleural effusion, hoarseness due to tumor disturbance in the recurrent laryngeal nerve, and dyspnea and hypoxia from diaphragmatic paralysis due to the involvement of the phrenic nerve.

Superior vena cava (SVC) syndrome results from compression or invasion of the SVC and can cause headache or a head-fullness sensation, facial or upper extremity swelling, supine breathlessness and flushing (plethora). Physical signs of SVC syndrome include facial and upper extremity edema, dilated neck and subcutaneous veins over the face and upper trunk, and facial and trunkal plethora.

Apical tumors, usually NSCLC, can invade the brachial plexus, pleura, or the ribs, causing shoulder and upper extremity pain and weakness or atrophy of the ipsilateral hand ( Pancoast’s tumor). Homer’s syndrome ( ptosis, miosis, enophthalmos, and anhidrosis) results when the paravertebral sympathatetic chain or cervical stellate ganglion is involved. Spread of tumor to the pericardium may be asymptomatic or lead to constrictive pericarditis or cardiac tamponade.  Seldom, esophageal compression causes dysphagia.

In Metastases:

Metastases sooner or later cause symptoms that vary by location. Metastasis to the liver causes pain, GI symptoms, and hepatic insufficiency. Metastases to the brain cause behavioral changes, confusion, aphasia, seizures, paresis or paralysis, nausea and vomiting, and coma and death. Bone metastases can lead to severe pain and pathologic fractures. While lung cancer commonly metastasizes to the adrenal glands, it seldom leads to adrenal insufficiency.

Paraneoplastic Syndromes:

These are symptoms that occur at sites distant from a tumor or its metastases. General paraneoplastic syndromes in patients with lung cancer include hypercalcemia ( in patients with squamous cell carcinoma, which results because the tumor produces parathyroid hormone-related protein), syndrome of inappropriate antidiuretic hormone secretion (SIADH), finger clubbing with or without hypertrophic pulmonary osteoarthropathy, hypercoagulability with migratory superficial thrombophlebitis ( Trousseau’s syndrome), myasthenia ( Eaton-Lambert syndrome), and various neurologic syndromes, including neuropathies, encephalopathies, encephalitides, myelopathies, an cerebellar disease. Mechanisms for neuromuscular syndromes involve tumor expression of autoantigens with production of autoantibodies, but the cause of most others is unknown.

DIAGNOSES FOR LUNG CANCER

• Chest x-ray
• CT or Combines PET-CT
• Cytopathology examination of pleural fluid or sputum
• Usually bronchoscopy- guided biopsy and fine-needle aspiration
• Sometimes open lung biopsy

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

CT exhibits many characteristic anatomic patterns and appearances that may confirm the diagnosis. CT also can guide needle biopsy of accessible lesions and is useful for staging. If a lesion found on a plain x-ray is highly likely to be lung cancer, a PET-CT scan may be done. This study combines anatomic imaging from the CT scan with functional imaging from the PET scan. The PET images can help distinguish inflammatory and malignant processes.

The technique used to obtain cells or tissue for confirmation depends on the accessibility of tissue and the location of lesions. Sputum or pleural fluid cytology is the least invasive technique. In patients with productive cough, sputum specimen is obtained on awakening may contain high concentrations of malignant cells, but yield for this method is less than 50% overall; a malignant effusion is a poor prognostic sign. In general, false -negative cytology readings can be minimized by obtaining as large a volume of sputum or fluid as possible early in the day and sending the sample to the pathology laboratory immediately to minimize delays in processing, which lead to cell breakdown.

A percutaneous biopsy is the next least invasive procedure. It is more useful for metastatic sites (supraclavicular or other peripheral lymph nodes, pleura, liver, adrenals) than for lung lesions because of the 20 to 25% risk of pneuomothorax and also the risk of negative results.

Bronchoscopy is the procedure often used for diagnosing lung cancer. In theory, the procedure of choice for obtaining tissue is the one that is least invasive. In practice, bronchoscopy is important for staging. A combination of washings, brushings, biopsies, and fine needle aspirations of visible endobronchial lesions and of paratracheal, subcarinal, mediastinal, and hilar lymph nodes often yields a tissue diagnosis.

Mediastinoscopy is the gold standard test for evaluating mediastinal lymph nodes but is a high-risk procedure, which is typically used before surgery to confirm or rule out the presence of tumor in enlarged mediastinal lymph nodes.

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

SCREENING FOR LUNG CANCER

No screening studies are generally accepted for healthy patients who do not have lung cancer. Clinical trials have evaluated screening chest x-rays in high- risk patients (like smokers) to try to detect lung cancer at earlier stages, but mortality did not decline. Screening CT scans are being evaluated because they are more sensitive, but CT produces more false-positive readings, which increases the number of needless invasive diagnostic procedures needed to verify the CT findings. Such procedures are costly and risk additional complications. A strategy of yearly CT screening of smokers with follow-up PET scan or high resolution CT (HRCT) to evaluate undefined lesions is currently being studied. So far, this strategy does not seem to lessen mortality and cannot be recommended as routine practice. The future of screening may lie in a combination of molecular analysis for genetic markers (such as K-ras, p53, EGFR), sputum cytometry, and detection of cancer-related volatile organic compounds such as alkane and benzene in exhaled breath.

STAGING OF LUNG CANCER

For SCLC, there are two stages, limited and extensive. Limited- stage SCLC disease is cancer restricted to one hemithorax (including ipsilateral lymph nodes) that can be enveloped within one tolerable radiation therapy port, unless there is a pleural or pericardial effusion. Extensive-stage disease is cancer outside a single hemithorax or the presence of malignant cells detected in pleural or pericardial effusions. Less than 1/3 of patients with SCLC will present with limited-stage disease; the remainder of patients often has extensive distant metastases.

For NSCLC, there are four stages, I through IV. Staging is based on tumor size, tumor and lymph node location, and the presence or absence of distant metastases.

Tests for initial evaluation and staging: All lung cancer patients need whole-body imaging. Different combinations of tests can be done. Some tests are done routinely, and others are done depending on whether the results would impact treatment decisions:

• Pet scan or integrated PET-CT
• CT from neck to pelvis ( done if PET-CT is not available)
• MRI of chest ( for tumors near apex or diaphragm to evaluate vascular supply)
• Biopsy of questionable nodes (if PET is indeterminate)
• Bone scan ( done with CT scans if PET-CT is not available)
• Head CT or brain MRI

Measurement of serum Ca, alkaline phosphatase, liver function, immune system, kidney function, platelets, Hb, and electrolytes are required to assist with treatment decisions.

If a PET-CT is not available, thin-section CT scanning from the neck to the upper abdomen (to detect cervical and supraclavicular and hepatic and adrenal metastases) is the one of the first staging tests for both SCLC and NSCLC. However, CT scans often cannot distinguish post-inflammatory changes from malignant intrathoracic lymph node enlargement or benign lesions from malignant hepatic or adrenal lesions (distinctions that determine stage). Thus, other tests are usually done when abnormalities are present in these areas. PET scanning is a reasonably accurate, noninvasive test used to identify malignant mediastinal lymph nodes and other distant metastases (metabolic staging). Integrated PET-CT scanning, in which PET and CT images are combined into a single image by scanners in a single gantry, is more accurate for NSCLC staging than CT or PET alone or than visual correlation of the 2 tests. The use of PET and integrated PET-CT is limited by cost, availability, and specificity (e.g. the test is quite sensitive and has an excellent negative predictive value, but its positive predictive value is not as high). When PET scan results are indefinite, bronchoscopy, mediastinoscopy, or video-assisted thoracoscopic surgery (VATS) can be used to biopsy questionable mediastinal lymph nodes. Without PET scanning, hepatic or adrenal lesions must be evaluated by needle biopsy.

MRI of the chest is slightly more accurate than high-chest HRCT for staging apical tumors and cancers close to the diaphragm and provides an evaluation of the vasculature surrounding the tumors.

Blood tests are usually done. Ca and alkaline phosphates levels, if elevated, suggest possible bony metastases. Other blood tests, such as CBC, serum albumin levels, AST, ALT, total bilirubin, electrolytes, and Creatinine levels, have no role in staging but  provide important prognostic information about the patient’s ability to tolerate treatment and may demonstrate the presence of paraneoplastic syndromes.

All patients with suspected lung cancer should undergo brain imaging. Brain imaging is especially necessary in patients with headache or neurologic abnormalities. Patients with bone pain or elevated serum Ca or alkaline phosphatase levels should undergo a PET-CT or a radionuclide bone scan if PET-CT is not available.

PROGNOSIS OF LUNG CANCER

The overall prognosis for lung cancer is poor. The median survival time fir limited-stage SCLC is 20 months, with a 5- year survival rate of 20%. Patients with extensive-stage SCLC do especially poorly, with a 5-year survival rate of <1%.

TREATMENT OF LUNG CANCER

• Surgery (depending on cell type and stage)
• Chemotherapy
• Radiation therapy

Treatment varies by cell type and by stage of disease. Many patient factors not related to the tumor affect treatment choice. Poor cardiopulmonary reserve, undernutrition, frailty or poor physical performance status, comorbidities, including cytopenias, and psychiatric or cognitive illness all may lead to a decision for palliative over curative treatment or for no treatment at all, even though a cure with aggressive therapy might technically be possible.

Radiation therapy carries the risk of radiation pneumonitis when large areas of the lung are exposed to high doses of radiation over time. Radiation pneumonitis can occur up to 3 months after treatment is completed. Cough, dyspnea, low-grade fever, or pleuritic chest pain may signal the condition, as may crackles or a pleural friction rub detected on chest auscultation. Chest x-ray may have nonspecific findings; CT may show a nonspecific infilitrate without an obvious mass. The diagnosis is often one of exclusion. Radiation pneumonitis can be treated with a corticosteroid taper over several weeks and bronchodialators for symptom relief.

Multiple chemotherapy regimens exist for treatment of lung cancer. In addition to standard chemotherapy drugs, several biologic agents that specifically target lung tumors are under investigation. EGFR tyrosine kinase inhibitors may be used in patients who have not responded to platinum-based or docetaxel therapy. Bevacizumab, a vascular endothelial growth factor inhibitor, is now used in combination with standard chemotherapy regimens in certain patients. Many other biologic agents are under investigation, including some that specifically target cancer cell signal transduction pathways or the angiogenesis pathways that supply O2 and nutrition to growing tumor cells.

Radiofrequency ablation, in which high- frequency electrical current is used to destroy tumor cells, is a newer technique that can sometimes be used in patients who have small early- stage  tumors or small tumors that have recurred in a previously irradiated chest. This procedure may preserve more lung function than open surgery does and, because it is less invasive, may be appropriate for patients who are not candidate for open surgery.

The bottom module stirs under the educational group.