Clinical Presentation and Prognostic Factors in Lung Cancer

Cough

One of the most common symptoms related to lung cancer is cough, which is reported in up to 60% to 70% of people at the time of diagnosis. Increased awareness of cough may help in the earlier detection of lung cancer, resulting in better outcomes, as was demonstrated in a recent United Kingdom Cough Awareness Campaign. Cough is most often caused by larger, centrally located bronchial mucosa invading lung tumors, but may also be present in smaller, peripheral lung tumors. A copious production of thin, colorless sputum (bronchorrhea) may be found in some patients with lung adenocarcinoma with a predominant lepidic growth pattern, but this is rare. Smaller but predominantly endobronchially located lung tumors may also cause cough. This cough may be either dry or nonproductive, but may be productive if respiratory infections occur as a consequence of the obstruction. Because cough is also a predominant symptom in other lung diseases such as COPD, it is sometimes difficult to recognize cough as a presenting symptom of lung cancer. When recording the medical history of the patient, special attention should be given to the changing cough pattern that may occur in patients with COPD or active smokers in whom lung cancer develops. The failure of an acute COPD exacerbation to resolve with adequate therapy should raise suspicion of an underlying respiratory malignancy.

Hemoptysis

Hemoptysis is not only a common symptom in up to one-third of people at the time of lung cancer diagnosis, but is also the only symptom that typically causes people to be prompt in reporting to their primary care physician. Approximately 20% of all cases of hemoptysis are associated with lung cancer; therefore, the occurrence of hemoptysis in a patient presenting to a primary care physician should always lead to further investigation, starting with chest x-rays. Hemoptysis usually results from tumor necrosis, growth of new blood vessels in and around the tumor (neovascularization), and bronchial mucosa ulceration with erosion and invasion of bronchopulmonary vessels. It may also be caused by an obstructive pneumonia or by paraneoplastic pulmonary embolism. At presentation, hemoptysis may vary from mild (blood-streaked sputum) to moderate and severe blood loss. Fortunately, severe or massive hemoptysis (more than 200 mL of blood expectorated at once or over the course of 24 hours or 5–10 mL/h of blood expectorated over 24 hours) occurs rarely at initial presentation, but it may become an increasingly life-threatening problem during the palliative treatment phase of an advanced lung cancer. Treatment of massive hemoptysis at the time of diagnosis of lung cancer of an unknown stage or of a potentially curable, newly diagnosed lung cancer will require prompt securing of the airways by endotracheal intubation and maintaining of optimal oxygenation before more definitive alleviation of the hemoptysis by either endobronchial therapy or by urgent surgical intervention can be offered. Moderate hemoptysis caused by tumors that cannot be reached by bronchoscope can be treated with bronchial artery embolization. For all other cases of endobronchial tumors causing hemoptysis, several endobronchial therapeutic modalities exist, ranging from photocoagulation with neodymium:yttrium aluminum garnet (Nd:YAG) laser to electrocautery to argon plasma coagulation. For distal or parenchymal-situated unresectable lung tumors, external-beam radiotherapy may be recommended. Endobronchial brachytherapy has been used for the palliative treatment of hemoptysis caused by endobronchially visible tumors, and the combination of high-dose-rate brachytherapy with external-beam radiotherapy demonstrated better symptom control than with external-beam radiotherapy alone. In a recent Cochrane meta-analysis, external-beam radiotherapy alone was found to be more efficient for palliation compared with endobronchial brachytherapy alone, although there was insufficient evidence to support the superiority of the two modalities combined for palliative symptom relief compared with external-beam radiotherapy alone.

Chest Pain

People with early-stage lung cancer may note vague, persistent chest pain or chest discomfort, even though no invasion of the chest wall, mediastinum, or pleura can be found. The true origin of this pain sensation is not completely understood, as no pain fibers are present in the lung parenchyma. Peribronchial autonomic nerves are able to transmit sensations of discomfort via the vagus nerve, which may also cause rare craniofacial pain sensations in nonmetastatic lung cancers. When further tumor growth occurs with local-regional invasion, such as in the pleura, mediastinum, or chest wall, more severe local pain symptoms may occur, requiring adequate analgesic treatment in combination with tumor-directed therapy.

Dyspnea, Stridor, Wheezing

Dyspnea is a common presenting symptom of lung cancer, occurring in up to 60% of people. The causes of dyspnea are often multifactorial, related to the increasing tumor volume, endobronchial tumor obstruction causing parenchymal atelectasis, lymphangitic tumor spread in a lobe or the entire lung, or pulmonary artery embolism. When lung cancer starts its local–regional invasion into the trachea, pericardium, and pleura, dyspnea may become more severe. Besides the tumor-related causes of dyspnea, there may be other potential aggravating causes, particularly in people with lung cancer who have COPD or cardiac conditions. When a tumor occludes the lower trachea or a major central airway, an acute feeling of breathlessness can occur along with the typical sound of stridor (in cases of severe occlusion of the airway or trachea) or unilateral monophonic wheeze (in cases of left- or right-sided main airway subocclusion). Standard treatment of the underlying cancer in people with early-stage or locally or regionally advanced disease will treat the dyspnea as well. For people with more advanced and symptomatic lung cancer, early palliative treatment of dyspnea (home oxygen therapy for hypoxemia, opioids, or inhaled furosemide) should be considered.

Hoarseness

The left vocal cord is stimulated by the left recurrent laryngeal nerve, which passes deep into the left thoracic cavity and under the aortic arch before again climbing up to the left vocal cord. Enlarged lymph nodes in the aortic pulmonary window or a large, invasive tumor to the left of the aortic branch may cause left recurrent nerve entrapment, resulting in nerve palsy and vocal cord paralysis. This vocal cord paralysis—occurring in fewer than 10% of people with lung cancer—results in hoarseness and sometimes also cough and aspiration. On a combination ¹⁸ F-2-deoxy- d -glucose (FDG)-positron emission tomography (PET)-CT, the internal laryngeal muscles on the opposite side of the entrapped recurrent laryngeal nerve (usually the left one) may present with false-positive increased FDG uptake because of the compensatory laryngeal muscle activation caused by the contralateral paralyzed vocal cord. Entrapment of the right recurrent laryngeal nerve by lung tumor tissue occurs much less frequently because this nerve does not extensively run through the right side of the chest.

Pleural Effusion

Lung cancer is one of the most common etiologies for a malignant pleural effusion. Malignant pleural fluid accumulation will eventually develop in 7% to 23% of people with lung cancer, but not all of them will be symptomatic at the time of diagnosis. Patients with a pleural fluid accumulation will generally report dyspnea, cough, chest pain, fatigue, and weight loss. The accumulation of malignant pleural fluid may be by direct invasion of the tumor into the pleura or by metastasis into the pleura ( Fig. 20.1 ). Pleural fluid accumulation may also have other causes in people with lung cancer, and these causes should be excluded: chylothorax by lymphatic obstruction or nonmalignant causes such as heart failure, pleuropulmonary infection, pulmonary infarction, and cirrhosis. Diagnostic thoracocentesis is therefore necessary to document the presence of malignant cells. In 40% to 50% of cases, the results of cytology examination will be false-negative and diagnostic medical thoracoscopy should be done to obtain a new sampling of pleural fluid combined with pleural biopsy to be examined. When the pleural effusion is confirmed as malignant, the lung cancer should be classified as stage IV (M1a), which is associated with a poor prognosis. Besides systemic therapy (chemotherapy, targeted therapy), treatment of malignant pleural effusion consists of fluid drainage and pleurodesis. Optimal treatment depends on an individual patient’s symptoms, performance status, and prognosis. For patients with a very poor prognosis (less than 3 months), repeated thoracenteses may be performed to alleviate dyspnea and pain. However, for most patients with lung cancer, a more definitive therapy for the malignant pleural effusion should be planned, either by talc slurry instillation via chest tube, thoracoscopy, or by insertion of an indwelling pleural catheter. The latter procedure is necessary in the event of lung entrapment by widespread pleural involvement.

Pericardial Effusion

Pericardial effusion occurs in 5% to 10% of people with lung cancer ( Fig. 20.1 ). Pericardial invasion by malignant cells occurs either by direct tumor invasion or by hematogenous or lymphatic spread of cancer cells. Patients who have pericardial effusion at presentation will either be asymptomatic (with only radiographic documentation of the presence of pericardial fluid) or they will report symptoms such as increasing dyspnea (up to grade 3/4), orthopnea, anxiety, palpitations, and retrosternal pain. On physical examination, specific signs of right-sided heart failure, arrhythmias (atrial fibrillation), and pericardial tamponade (pulsus paradoxus) may be found. Cardiac tamponade should be regarded as a life-threatening condition requiring immediate intervention. A suspected diagnosis of severe pericardial effusion should prompt investigation by echocardiography to document this effusion. When a right-sided ventricular collapse is found, urgent pericardiocentesis should be performed to provide relief. Following initial puncture, a pericardial catheter may be inserted for further fluid drainage. Recurrence of fluid accumulation after pericardial drainage has been performed may occur in one-third of patients. After recurrence, a new pericardial puncture may be performed together with the instillation of a sclerosing agent (e.g., cisplatin, mitoxantrone). Another treatment approach for patients with a better prognosis and a refractory pericardial effusion may be video-assisted surgical thoracoscopy with a pericardiotomy (pericardial window).

Superior Vena Cava Syndrome

Obstruction or compression of the venous return from the head via the superior vena cava is a common complication of lung cancer. However, superior vena cava syndrome (SVCS) is rarely present (fewer than 5% of cases) at the time of initial lung cancer diagnosis. Lung cancer is the cause of SVCS in about 50% of cases, but other intrathoracic malignancies such as lymphoma, primary mediastinal tumors, and metastatic tumor in the mediastinum should be excluded as the cause. SVCS results from a growing right upper lobe lung tumor that extends centrally to the superior vena cava or by growing, malignant right paratracheal lymph nodes. An intraluminal thrombus may also form. Nonsmall cell lung cancer (NSCLC) causes SVCS more frequently than small cell lung cancer (SCLC). The clinical presentation of SVCS typically involves swelling of the head and neck, edema of the eyelids, distention of the veins in the neck and on the chest wall, cough, breast swelling, dizziness, headache, blurred vision, dyspnea, dysphagia, and chest pain. When tumor growth is aggressive, symptoms may appear more rapidly because of lack of time for collateral circulation to develop proximal to the venous obstruction, particularly when the obstruction is situated above the level of the junction with the azygos vein. Diagnosis of SVCS can be easily documented by chest CT ( Fig. 20.2 ), but a histologic diagnosis of the underlying cancer is mandatory before treatment can be initiated. Treatment of SVCS consists of alleviating symptoms as well as treating the underlying lung cancer. In the case of a local–regionally advanced lung cancer, chemoradiation therapy can be initiated. For an advanced lung cancer (especially for a SCLC), chemotherapy may begin immediately. When the patient is highly symptomatic, more rapid symptom relief can be achieved by placement of an endovascular stent than by chemoradiation therapy. Patients who present with stridor as a result of central airway obstruction or severe laryngeal edema, as well as patients who are in a coma caused by cerebral edema, should be immediately treated with endovascular stenting. This procedure can be performed with use of different types of stents (e.g., stainless steel stents such as Gianturco, Wallstent, or Palmaz); however, nitinol stents currently appear to be more suitable for the safe and efficient endovascular management of SVCS. Success rates associated with first stenting have ranged from 80% to 95%. Although the average risk of SVCS recurrence after stenting is 10% to 14%, recurrence can almost always be resolved by a new stenting procedure.

Pancoast Syndrome

A lung cancer that grows in the apex of the upper lobe toward the superior sulcus, ribs, and vertebrae will cause pain in the shoulder, scapula, and chest wall. Invasion of the brachial plexus (specifically the lower nerve roots of the ulnar nerve) will result in radiating pain and muscle wasting in the arm and hand. Horner syndrome, by invasion of the sympathetic chain and stellate ganglion, results in ptosis, miosis, and hemifacial anhidrosis, and may be part of the so-called Pancoast syndrome. Typically, patients with Pancoast syndrome will have consulted other specialists before a final diagnosis of lung cancer is made, sometimes with a delay as long as 1 year from the time pain first occurred. Most people with lung cancer who present with Pancoast syndrome have NSCLC. Pancoast syndrome as an initial clinical presentation of lung cancer occurs in about 4% of cases.

Dysphagia

Dysphagia may occur when the esophagus becomes obstructed by enlarged mediastinal lymph nodes or by a lung tumor invading the esophagus. Recurrent laryngeal nerve palsy may also cause dysphagia because of dysfunction of the laryngeal swallowing mechanism. Patients will typically note increasing difficulty swallowing and may subsequently become incapable of swallowing. Therapy consists of treatment of the underlying local–regionally invasive lung cancer and temporary parenteral feeding, if necessary. Occasionally, palliative esophageal stenting is needed.

Diaphragmatic Paralysis

When the phrenic nerve gets trapped by a growing primary tumor or by bulky lymph nodes (typically originating from the aortic–pulmonary window lymph nodes), the diaphragm may become paralyzed, resulting in an increase in dyspnea. Lung cancer invading the phrenic nerve is therefore an indication of locally advanced disease and should be staged as a cT3 tumor according to the International Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) classification eighth edition.

Bone Metastases

Bone metastases develop in approximately 30% to 40% of people with advanced NSCLC, with metastases either present at the time of diagnosis or developing during the course of the neoplastic disease. Compared with bone scans, PET has similar sensitivity (at least 90%), but a higher specificity (at least 98%) and accuracy (at least 96%), and is therefore considered superior for detecting bone metastases. Therefore, if no abnormality in bones is found on a PET scan of a patient who has no signs or symptoms suggestive of bone metastases, a bone scan is not needed. Lung cancer metastases to bone are predominantly lytic.

Bone metastases cause significant pain and morbidity and are characterized by various skeletal-related events, including pathologic fractures, spinal cord compression, the need for radiation or surgery of the bone, and hypercalcemia of malignancy. Periosteal inflammation and elevation is the mechanism that most frequently causes pain from bone metastases. Pain that cannot be controlled with nonsteroidal anti-inflammatory drugs should be managed with narcotic analgesics. Most patients with symptomatic bone metastases achieve some pain relief with a low-dose, brief course of radiation therapy, as demonstrated in a trial from the Radiation Therapy Oncology Group (RTOG 97-14), which included patients with breast cancer or prostate cancer. In this trial, the efficacy of 8 Gy in a single fraction was comparable to that of the standard treatment course of 30 Gy delivered in 10 treatment fractions over 2 weeks in terms of response rates and the incidence of subsequent pathologic fractures. However, the retreatment rate was significantly higher in the 8-Gy arm (18% vs. 9%; p < 0.001). Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment for bone metastases, and several randomized trials have shown promising results. In particular, the focal nature of SABR provides an otherwise unavailable noninvasive treatment option for previously radiated spinal metastases. For select patients with weight-bearing bone metastases at special risk of pathologic fracture, surgical operation may be considered. Vertebral augmentation procedures (kyphoplasty and vertebroplasty) are also important modalities when treating symptomatic vertebral compression fractures. In addition to the immediate pain relief, these procedures have several advantages, including applicability in previously radiated sites, the possibility of outpatient care, and obtaining of tissue biopsy specimens. Bisphosphonates (pamidronate and zoledronic acid) play an important role by preventing bone resorption at sites of bone remodeling. In one study, zoledronic acid was associated with a significantly lower incidence of skeletal-related events among patients with NSCLC with bone metastasis. Denosumab, another drug in a novel class of bone-targeting agents, is designed to inhibit receptor activator of nuclear factor kappa-B ligand. Compared with zoledronic acid, denosumab prolonged overall survival of patients with NSCLC with bone metastases.

Brain Metastases

Lung cancer is the most common cause of brain metastases. Metastases to the brain are usually symptomatic, and more than two-thirds of patients with brain metastases have some neurologic symptoms during the course of their illness. The clinical manifestations of brain metastases are variable depending on the location of the lesion and the degree of associated edema. Headache is a common presenting symptom and occurs more often with multiple metastases. Focal or generalized seizures have occurred in approximately 10% of patients by the time of presentation. Other symptoms of brain metastases include nausea and vomiting, focal weakness, confusion, ataxia, or visual disturbance. The signs and symptoms of brain metastases are often subtle; therefore, brain metastases should be suspected in all patients with lung cancer in whom neurologic symptoms develop. Magnetic resonance imaging (MRI) is currently the criterion standard for the diagnosis of brain metastases.

Corticosteroids can rapidly decrease the symptoms associated with brain metastases by decreasing peritumoral edema. Patients with seizures should be treated with antiepileptic medication. Subsequent treatment should be used according to size, number, and location of lesions as well as the extracranial disease status and performance status of the patient. Treatment modalities for brain metastases include whole-brain radiotherapy, stereotactic radiosurgery, and surgical resection. Stereotactic radiosurgery should be considered before whole-brain radiotherapy for patients with one to three brain metastases.

Leptomeningeal carcinomatosis is not rare in NSCLC and continues to be a devastating end-stage complication of the disease. Further improvements in systemic treatment may lead to prolonged survival for more patients with stage IV disease; therefore, when all existing therapies have failed in these patients, leptomeningeal carcinomatosis may be more likely to develop. The most common ways for malignant cells to gain access to the subarachnoid space are by direct extension from preexisting tumors or by hematogenous dissemination. A high index of suspicion is required to make an early diagnosis of leptomeningeal carcinomatosis as there is a variety of neurologic manifestations. Headache, changes in mental status, cranial nerve palsies, back or radicular pain, incontinence, lower motor neuron weakness, and sensory abnormalities are typical symptoms. The most informative diagnostic tool in the evaluation of leptomeningeal carcinomatosis is lumbar puncture. The opening pressure should be measured and cerebrospinal fluid sent for cytologic examination, cell count, and measurement of protein and glucose. Positive findings on cerebrospinal fluid cytology examination are found on initial lumbar puncture in 50% of patients with leptomeningeal carcinomatosis and in approximately 85% of patients who have three high-volume lumbar punctures. Therefore, patients with clinical symptoms and signs suggestive of leptomeningeal carcinomatosis should have repeated lumbar puncture if the first cytology evaluation yields negative results.

Leptomeningeal carcinomatosis is a particularly difficult challenge in the treatment of cancer. Intrathecal chemotherapy has been the mainstay of treatment, even though the extent of its benefit has not been proven in randomized clinical trials. A ventriculoperitoneal shunt is also an effective palliative tool to decrease intracranial pressure. Given the dismal treatment outcome and prognosis of patients with leptomeningeal carcinomatosis, new therapeutic agents or strategies are urgently needed.

Spinal Cord Metastases or Spinal Compression

Spinal cord metastases or compression can be classified anatomically as intramedullary, leptomeningeal, and extradural. Extradural compression includes several mechanisms, such as continued growth of bone metastases into epidural space, blockage of neural foramina by a paraspinal mass, and destruction of vertebral bone. At the time of presentation, 90% of patients have local or radicular pain, and up to 50% of patients may have paralysis, sensory loss, and sphincter dysfunction. If the clinical suspicion of spinal cord compression is high, immediate high-dose dexamethasone should be administered before compression is confirmed radiographically. Radiotherapy is the mainstay of treatment for spinal cord metastases and should be started immediately after MRI confirmation of spinal cord compression. For patients with lung cancer who have symptomatic epidural spinal cord compression and good performance status, a neurosurgical consultation is recommended and, if appropriate, surgery should be performed immediately, followed by radiotherapy.

Liver and Adrenal Gland Metastases

Liver involvement occurs frequently with lung cancer. Patients may have upper quadrant or epigastric discomfort as a result of large metastases. Most liver metastases are asymptomatic, and some patients experience vague symptoms such as fatigue, weight loss, and nausea. Liver dysfunction occurs only in the presence of extensive metastases.

The type of cancer most often associated with adrenal metastases is lung cancer, followed by gastric cancer. Adrenal metastases are usually detected on CT scans, and bilateral metastases appear in approximately half of patients with lung cancer. In most cases, these lesions are asymptomatic, although large metastatic masses may cause pain. Adrenal insufficiency is rare even in bilateral metastases because functional adrenal cortical loss occurs only when more than 90% of the adrenal gland has been destroyed. However, adrenal insufficiency should be suspected in patients who present with appropriate clinical symptoms and bilateral adrenal metastases. Anecdotal reports have suggested that long-term survival can occur after resection of isolated adrenal metastasis from NSCLC, but this has not been confirmed by randomized clinical trials and the chance of selection bias should be considered.

Other Metastatic Sites

Lung cancer metastases may occur at other sites, such as skin, soft tissue, pancreas, intraabdominal lymph nodes, bowel, ovaries, and thyroid. Management of these metastatic sites is primarily based on the patient’s symptoms.

Dermatologic or Musculoskeletal Disorders