The Assessment of the Person With Lung Cancer and Implications for the Rehabilitation Clinician

Introduction

Lung cancer patients are often diagnosed later in life and at advanced stages of the disease. The treatment of lung cancer often consists of a combination of systemic therapy (chemotherapy, immunotherapy), radiation therapy, and surgery. These treatments as well as age-related changes, comorbid conditions such as emphysema and heart disease can have adverse effects on physical function. Cancer and cancer treatment–related physical impairments can develop and can lead to a decreased quality of life. This chapter provides an overview of the anatomy and physiology of lung cancer, toxicities associated with common lung cancer treatments, and then provides a framework for the assessment of lung cancer patient from a holistic perspective.

Epidemiology of Lung Cancer

Lung cancer is the most common cause of cancer mortality in the United States. The age of its occurrence is 50–70 years, with the mean age of presentation being 60 years. The risk of developing lung cancer is higher among men in all age groups over 40, and is more common in men than in women. In the United States, Northern Europe, and Western Europe, the prevalence of lung cancer has been decreasing in men; however, the incidence of lung cancer has been increasing in Eastern and Southern Europe. Western countries are seeing an increase in prevalence of lung cancer in women, as well as in younger individuals. Women have a higher incidence of localized disease at presentation, higher incidence of adenocarcinoma, and are typically younger when they present with symptoms. Over the past 20 years, the incidence of lung cancer has generally decreased in both men and women 30–54 years of age in all races and ethnic groups, with the incidence declining more steeply in men. Rates of incidence in women, ages 30–39 years, have increased when compared to those in men of the same age group.

The predominant risk factors for lung cancer are cigarette smoke, asbestos, and radon exposure. Radioactive decay of uranium results in the production of radon. Asbestos and arsenic are carcinogens and are risk factors associated with occupational exposure. Pack-years, or the amount smoked × duration of smoking, are directly related to risk of lung cancer.

It has been estimated that 10%–15% of all lung cancers occur in those who have never smoked, resulting in the mortality of 16,000–24,000 people. Those who do not smoke still have the potential to be exposed to secondhand smoke, radon, and indoor air pollutants such as cooking fumes. The risk of developing lung cancer in those who have never smoked increases by 20%–30% when exposed to secondhand smoke at home or at work. The likelihood of developing lung cancer due to secondhand smoke increases in the same manner it does for those who smoke, with greater duration and levels of exposure leading to increased risk.

Types of Lung Cancer

Small cell carcinoma represents approximately 15% of lung cancer cases and is treated with chemotherapy and radiation, and does not involve surgical resection. On histology, poorly differentiated small cells are observed that are derived from neuroendocrine cells. This type of cancer has a primary tumor located centrally within the lung and is common among male smokers.

Nonsmall cell carcinomas compose the other 85% of all lung cancers, with 40% being adenocarcinoma, 30% squamous cell carcinoma, 10% large cell carcinoma, and 5% carcinoid tumor. Squamous cell carcinoma has keratin pearls or intracellular bridges on histology and is the most common tumor in male smokers. The primary tumor in squamous cell carcinoma is centrally located within the lung and may produce PTHrP which is associated with hypercalcemia. Treatment of squamous cell carcinoma is through surgical resection, chemotherapy, and radiation.

Adenocarcinoma is the most common tumor in nonsmokers as well as female smokers, with a peripherally located primary tumor. A peripheral mass along with pleural plaques can cause the pleura to “pucker.” This can also be seen as a result of asbestosis. Adenocarcinoma in situ exhibits columnar cells growing along bronchioles and alveoli which can present on imaging as a consolidation that can resemble a pneumonia. Treatment of adenocarcinoma is chemotherapy, radiation, and resection/surgery.

Large cell carcinoma is identified by poorly differentiated large cells. This type of carcinoma has an association with smoking and has a primary tumor that can be located either centrally or peripherally in the lung. When a primary tumor's location is described as central, this pertains to the trachea, bronchi, or segmental bronchi, while a peripherally located primary tumor will be at the subsegmental bronchi and distal structures within the lung.

Carcinoid tumors appear as well-differentiated neuroendocrine cells on histology and have no significant association with smoking. The primary tumor can be located centrally or peripherally within the lung; however, when located centrally, it forms a poly-like mass in the bronchus.

Staging of Lung Cancer

Staging of lung cancer is vital in order to provide the most appropriate treatment. Staging via PET-CT occurs before treatment and is performed utilizing the TNM staging system. T is indicative of the primary tumor size and local extension. N represents spread to regional lymph nodes. In the case of lung cancer, this refers to hilar as well as mediastinal lymph nodes. N0 represents no regional lymph node metastasis, N1 is ipsilateral peri-bronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, N2 is ipsilateral mediastinal and/or subcarinal nodes, and N3 is contralateral node involvement or ipsilateral scalene node involvement or supraclavicular node involvement. M indicates the presence of metastasis with M0 representing no metastasis and M1 representing distant metastasis.

Lung Anatomy and Physiology

It is important to understand basic principles of lung anatomy and physiology to grasp the changes that take place to the pulmonary system when affected by cancer. As air enters through the pharynx, the first structures encountered are the trachea and bronchial tree. The tracheal mucosa is composed of ciliated pseudostratified columnar epithelium and numerous mucus-secreting goblet cells on a basement membrane with a thin collagenous lamina propria. The submucosa contains sero-mucous glands and the adventitia contains cartilaginous rings interconnected by connective tissue. The hyaline cartilage rings are opened posteriorly with the open ends connected by fibro elastic tissue and a band of smooth muscle.

The trachea bifurcates at the carina into the left and right main bronchi. Each bronchus then has lobar branches extending into each respective lung. In order to pass more horizontally over the heart, the left main bronchus diverges from the bifurcation at a sharper angle. The right main bronchus separates into superior, middle, and inferior lobar bronchi, each corresponding to the lobes of the right lung. The left main bronchus separates into superior and inferior lobar bronchi, each corresponding to the lobes of the left lung. The conducting portion of bronchial tree is from the carina to the terminal bronchiole, with the responsibility of moving gas into and out of the lungs. This includes the segmental bronchus, which is covered by cartilaginous plates, the large subsegmental bronchus, and the small subsegmental bronchus. The epithelium of the bronchus is comprised of pseudostratified columnar ciliated epithelium with goblet cells, which transitions first into a simple columnar ciliated epithelium and then into a cuboidal epithelium as it moves distally, branching into smaller bronchioles. The cartilaginous support is lost at the bronchiolar level and the muscle layer becomes the dominant structure, which is made of smooth muscle and elastic fibers.

The terminal bronchiole is a part of the bronchiole that does not possess the cartilage plates of the more proximal portions of the bronchus and demarcates the end of the conducting portion of the airway and the beginning of the respiratory portion of the airway. Distal to the conducting portion of the airway, the respiratory portion of the airway is responsible for the transfer of oxygen and carbon dioxide and contains the respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli. Respiratory bronchioles are composed of pulmonary alveoli, smooth muscle, and elastic fibers. The epithelium of the respiratory bronchiole is primary cuboidal, may be ciliated, does not contain goblet cells, and has a supporting layer formed by collagen and smooth muscle. Alveoli interrupt the main wall and are the smallest and most numerous subdivisions of the respiratory system. The interalveolar septum contains openings between alveoli to promote equalization of air pressures among them.

Alveoli have an epithelial lining and lumen which contains alveolar macrophages, surfactant, type I and type II pneumocytes, elastic fibers, capillary endothelial cells, capillary lumens, and erythrocytes. Gas exchange occurs between alveolar and capillary lumens in the alveoli, during which oxygen is transferred to erythrocytes and carbon dioxide is transferred to the alveolar airway. Basement membranes of capillary endothelial cells are fused with the basement membrane of type I alveolar epithelial cells, which decreases distance for gas exchange at the air–blood barrier where gas exchange occurs. Type I pneumocytes are thin and squamous, joined by tight junctions to limit fluid infiltration into alveoli, and are responsible for gas exchange, maintenance of ion and fluid balance, and communication with type II pneumocytes. Type II pneumocytes are large and cuboidal, produce and secrete surfactant, express immuno-modulatory proteins required for host defense, and are responsible for the regeneration of alveolar epithelium following injury. Surfactant decreases surface tension of the alveoli, enabling easier lung expansion. (4).

As can be seen from staging of lung cancer, the lymphatic system is very important to the spread of lung cancer. Pulmonary lymph nodes along the bronchial tree drain from lungs into hilar (bronchopulmonary) lymph nodes. From there, lymph moves through inferior and superior bronchial nodes, paratracheal lymph nodes, the broncho–mediastinal trunk, and then to the right lymphatic or thoracic duct. (5).

The collection of alveolar sacs makes up an acinus. A combination of multiple acini, pulmonary arteries, pulmonary veins, and lymphatics make up the normal secondary pulmonary lobule, which is the functional unit of the lung.

Respiratory mechanics relates directly to the physiology of the lungs and is characterized by inspiratory and expiratory phases. In inspiration, the diaphragm contracts and lowers, thus increasing volume of the pleural cavity. The external intercostal scalene and posterior serratus muscles contract to elevate ribs and expand pleural cavity further. Expansion of pleural cavity generates negative intrapleural pressure and results in inspiration. Due to surface tension, increases in volume of pleural cavity coincide with increase in lung volume.

When the muscles previously described relax and diaphragm returns to superior expiratory position, this is referred to as passive expiration. Lung contraction increases pulmonary pressure and results in expiration. Contrast this with forced expiration, where internal intercostal muscles actively lower rib cage more than passive elastic recoil and more rapidly.

The entire bronchial tree moves within the lung as the volume of the lung changes throughout the inspiratory and expiratory process of respiration. As you move more distally along the bronchial tree, movements are more pronounced.

Anatomy, Physiology, and Pathophysiology of Lung Cancer

Now that the normal structure and function of the respiratory system has been described, the effects of cancer on anatomy and physiology, along with the pathophysiology of cancer itself, can be described. Carcinogens damage DNA, resulting in mutations that disrupt regulatory systems and enable growth and spread of cancer. Polycyclic hydrocarbons of cigarette smoke are known to be particularly carcinogenic. Uncontrolled cell growth in the lungs involves the structures and tissues of the lung itself, as well as the surrounding structures and their respective tissues. Cancer cells develop resistance to oxidative stress, which enables them to withstand and exacerbate inflammatory conditions that inhibit the activity of the immune system against the tumor.

Anatomic changes seen in lung carcinoma cause pathophysiologic variation that is similar to that which is observed in a myriad of other lung diseases. Imaging will show a solitary nodule, also known as a coin lesion. Coin lesions are also seen in granulomatous conditions, as well as in individuals with bronchial hamartoma. Nonspecific presenting symptoms such as cough, dyspnea, hemoptysis, obstructive pneumonia, and weight loss are seen in patients with lung carcinoma. As the disease progresses, increased invasion occurs that can affect several of the anatomical structures described above. An example of this is T2 in the staging of the lung cancer. This involves the main bronchus, invades visceral pleura, and or shows atelectasis/obstructive pneumonitis into the hilum. Invasion and expansion by the primary tumor can cause damage to structures typically used for defense of infection, resulting in pneumonia. Examples of defenses against pneumonia are cough reflex, muco-ciliary escalator, and mucus plugging (2). Inflammation that incorporates bronchioles and damages cells can perpetuate broncho-constriction and promote respiratory compromise.

The location of the cancer/tumor determines the signs/symptoms observed. An endobronchial location can present with cough, hemoptysis, bronchial obstruction, as well as pneumonitis, pneumonia, and/or pleural effusion. Mediastinal location can cause dyspnea, postprandial cough, wheezing, stridor, hoarseness, chylothorax, and dysphagia. Hoarseness typically occurs in this case due to irritation of recurrent laryngeal nerve. Upper airway obstruction is the cause of stridor and/or wheezing. Chylothorax relates to obstruction of lymph at the thoracic duct. A postprandial cough as well as dysphagia can be the result of enlargement of subcarinal lymph nodes and thus compression of the middle third of the esophagus. Bronchial and tracheal stenosis as result of cancer results in obstruction and thus changes in airflow and decreased oxygenation. Superior vena cava syndrome occurs when the tumor obstructs the superior vena cava, which results in distended head and neck veins, as well as blue discoloration of arms and face. Diaphragmatic paralysis can occur if the tumor is pressing on the phrenic nerve. Paralysis or weakness of the diaphragm impacts the respiratory mechanism and will lead to respiratory compromise. Horner syndrome presents with ptosis, anhidrosis, and miosis when the sympathetic chain is involved. Shoulder pain and hand weakness can be seen with brachial plexus involvement of apical tumors that involve the superior sulcus, also known as Pancoast tumors.

In adenocarcinoma, when the lung is biopsied, the histological analysis shows a tumor arising from the bronchial glands as well as substantial mucus production. Adenocarcinomas arise from acinar, papillary, broncho-alveolar, and mucus-secreting cells. Adenocarcinoma may spread directly to pleura, diaphragm, pericardium, or bronchi with advanced disease spreading to the mediastinum, great vessels, trachea, esophagus, vertebral column, or adjacent lobe. Spread can result in superior vena cava obstruction, phrenic nerve dysfunction, Horner syndrome, brachial plexus compression, and/or pericardial effusion (12).

Airway obstruction at any level interferes with one's oxygenation and ventilation ability. Any pathology that limits the flow of air into and out of the body will limit ventilation. Malignant airway obstruction can occur due to obstruction within central airways, which includes the trachea, main-stem bronchi, and right bronchus intermedius. Complications related to central airway obstruction include but are not limited to dyspnea, atelectasis, hypoxemia, hemoptysis, postobstructive pneumonia or respiratory distress.

Accumulation of inflammatory mucus and loss of elastic recoil due to lung tissue destruction and/or increased resistance within the airway causes pathology that is also seen in COPD. Patients with this condition will have permanent enlargement of air spaces beyond the terminal bronchioles, increasing diffusion distance, and thus worsening ventilation perfusion mismatch. Changes in pulmonary function tests (PFTs) observed due to this pathology are decreased functional vital capacity (FVC), decreased forced expiratory volume during first second of expiration (FEV1), decreased FEV1:FVC ratio, and increased total lung capacity (TLC) due to air trapping.

Inflammation in lung that exceeds ability of antiproteases to balance protease activity will lead to destruction of alveolar air sacs. Destruction of alveoli results in a decrease of surface area for gas exchange, which can cause necrotizing inflammation with damage to airway walls resulting in air trapping due to sustained dilation of bronchioles and bronchi, as well as loss of airway tone. Air trapping can result in hypoxemia, which can then lead to secondary pulmonary hypertension and progress to right-sided heart failure and further dyspnea on exertion.

Pleural effusion with inflammation, leaky capillaries, and increased oncotic pressure can result in decreased lung volume and restrictive lung disease. Restrictive lung disease reduces the total volume of air that the lungs can hold. Pathophysiology that is seen in these instances is poor lung compliance, as well as poor chest wall compliance, depending on if the restriction is intrinsic or extrinsic. PFT changes observed due to these changes are decreased TLC, residual volume (RV), FEV1, and normal or increased functional vital capacity (VC) ratio of FEV1:FVC. Lung cancer is an exudative process which leads to decrease in exchange of oxygen and thus ventilation mismatch. Decrease in ventilation can result in atelectasis and respiratory compromise.

Development of pneumonia or pneumonitis can cause alveoli to be filled with exudate, inflammatory cells, and fibrin. This process worsens ventilation mismatch and can cause changes in lung parenchyma which will decrease lung volume and cause further ventilation perfusion mismatch. Both diffusion defects and ventilation perfusion mismatch could lead to hypoxemia, which will cause hypoxia and eventual further cellular injury.