Lung cancer: Clinical practice

Lung cancer is the leading cause of cancer death worldwide in both males and females. It’s broadly classified into non-small cell lung cancer; accounting for 85% of all lung cancers, and small cell lung cancer, accounting for the remaining 15%.

Small cell lung cancers are centrally located in the lung. Non-small cell lung cancer is further subclassified into four subtypes, the most common one is adenocarcinoma, which usually develops at the periphery of the lung. There’s also the term bronchoalveolar carcinoma which refers to adenocarcinoma-in-situ, which is where the adenocarcinoma tumor isn’t quite as aggressive and hasn’t yet crossed the basement membrane. The other 3 subtypes of non-small cell cancer include squamous cell carcinoma and carcinoid tumors; which are usually centrally located, as well as the rare large cell carcinoma; which can be located either centrally or peripherally.

Now the most important risk factor for the development of lung cancer is tobacco smoking, which accounts for more than 90% of cases. This usually comes in the form of cigarettes, but also includes cigars, pipes, and hookah, also called shisha. There is a dose-dependent linear relationship between the pack-years - the number of cigarette packs per day times the number of years of smoking - and the risk of lung cancer. Second-hand smoking, which is involuntarily inhaling tobacco smoked by other people, also increases the risk of lung cancer.

Additionally individuals exposed to asbestos for a long period of time such as those working in shipbuilding or construction industry, are also at increased risk. Although classically associated with mesothelioma, which is a malignancy of the pleura, asbestos more commonly causes adenocarcinoma. Other risk factors include radon exposure, which is found in high concentrations in basements, as well as exposure of chest radiation, such as in treatment of lymphoma.

Individuals with lung cancer typically present with symptoms or are asymptomatic but have a suspicious nodule that’s found incidentally on chest imaging. The symptoms of lung cancer can be broadly classified into 5 categories. The first category includes local symptoms - like cough, hemoptysis, and shortness of breath. If the airway is obstructed by a growing tumor, then a person can also develop recurrent infections distal to the obstruction. The second category is constitutional symptoms, which includes fever, unintentional weight loss, and fatigue. These symptoms often indicate more advanced disease.

The third category is local invasion, which are symptoms from the tumor damaging surrounding mediastinal structures. For example, a tumor that pushes up against the superior vena cava, can cause SVC syndrome - where there’s shortness of breath and swelling of the face and arm. Another example is when a tumor pushes up against the phrenic nerve, causing paralysis of the hemidiaphragm, or when it pushes up against the recurrent laryngeal nerve, causing a hoarse voice.

Pancoast tumors, which are usually non-small cell lung cancers located peripherally can push up against the brachial plexus, causing shooting arm pain and weakness. Pancoast tumors can also damage the nearby cervical sympathetic chain, causing Horner’s syndrome, which causes ptosis, miosis, and facial anhidrosis. If the tumor invades into the pleura, then it can result in a pleural effusion, causing shortness of breath, pleuritic chest pain, and dullness on percussion.

The fourth category are symptoms due to distant metastasis. Lung cancer typically metastasizes in the brain, causing headaches and vomiting, the bone; which can cause pain or fractures, the liver, which can cause abdominal pain, or the adrenal gland; which is usually asymptomatic, but can cause adrenal insufficiency.

The fifth and final category are symptoms due to paraneoplastic syndromes, which can clue you towards a specific subtype of lung cancer. For example, small cell cancers are made of immature neuroendocrine cells, so they ectopically produce hormones, like antidiuretic hormone which leads to syndrome of inappropriate antidiuretic hormone secretion or SIADH, which results in hyponatremia, or adrenocorticotropic hormone which results in Cushing syndrome.

Small cell lung cancers can also cause the production of antibodies against the presynaptic calcium channels of the neuromuscular junction, causing Lambert-Eaton myasthenic syndrome. This results in less acetylcholine release from the presynaptic junction, causing muscle weakness. Usually the muscle weakness improves as an individual uses the affected muscle group, differentiating it from myasthenia gravis which has the opposite pattern.

Small cell lung cancer can also cause the production of antibodies against Hu-antigens which are found on neurons. If cerebellar neurons are mainly affected, it leads to symptoms like ataxia and nystagmus. If neurons in the cerebrum are affected, then it can lead to symptoms like dementia and seizures. Squamous cell lung cancers sometimes produce parathyroid hormone related peptide, or PTHrP, which mimics PTH, causing hypercalcemia and as a result of the negative feedback, it leads to low PTH levels.

Adenocarcinoma causes a paraneoplastic syndrome called hypertrophic osteoarthropathy which leads to fingernail clubbing, joint pain, and proliferation of long bone periosteum in the femur and tibia, causing bone pain. Large cell carcinoma can produce the beta subunit of human chorionic gonadotropin, or beta-hcG, which can cause gynecomastia in males or galactorrhea in females.

Finally, carcinoid tumors can secrete serotonin, causing carcinoid syndrome, which can lead to symptoms like flushing, wheezing, dizziness, and diarrhea. The serotonin can also induce fibrosis of the mitral and aortic valves. Often, elevated serotonin levels can be detected by screening the urine for a metabolite of serotonin, 5-hydroxyindoleacetic acid, or 5-HIAA.

In someone with symptoms of lung cancer, the first step is usually a chest x-ray. If there’s evidence of a pleural effusion, then a diagnostic thoracentesis can be done to obtain a sample of the pleural fluid. The fluid may have malignant cells, and if it does, then it means that the lung cancer has invaded into the pleura, which is a hallmark of metastatic cancer, and that has a poor prognosis.