BMS250_Week 5_L1_Pathophysiology of Lung Cancers Lander 2024.pptx

Pathophysiology of Major Neoplastic Diseases of the Lungs Daniel Lander, ND CCNM 2024 Learning Outcomes Briefly describe the pathogenesis, and relate it to the clinical features, and complications/prognosis of the following lung neoplasms: Adenocarcinoma, squamous cell carcinoma, large cell carcinom...

Pathophysiology of Major Neoplastic Diseases of the Lungs Daniel Lander, ND CCNM 2024 Learning Outcomes Briefly describe the pathogenesis, and relate it to the clinical features, and complications/prognosis of the following lung neoplasms: Adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, and carcinoid Compare the pathophysiological and clinical characteristics of metastatic lung cancer to primary lung cancer Briefly describe the pathophysiology of the common paraneoplastic syndromes that accompany lung cancer and relate to the major clinical features Cancers Affecting the Lungs Primary lung cancer Non-small cell lung cancer Small cell lung cancer Carcinoid Mesothelioma (pleura) Secondary (metastasized) lung cancer Other primary tumours that can affect the lungs (not discussed) Lymphomas Sarcomas Adenoid cystic carcinomas Epidemiology Lung cancer is the most common cause of cancer death in both men and women (worldwide and US and Canada) The peak age for lung cancer is between 60 and 70 years (rare under 40) Non-Small Cell Lung Cancer (historically reacted to chemo more slowly) The most common type of lung cancer, accounting for 80% of all lung cancers Three main subtypes: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Grouped together because of historically similar treatment (based on chemo agents and reactions between types. Not as relevant now) Pancoast tumours, also known as superior sulcus tumors are primary lung cancers that develop in the apex of the lung. they are usually non-small cell cancers, most often squamous cell carcinomas Adenocarcinoma (develop from the mucosal glands) Most common lung cancer in North America accounting for 36.4% of all lung cancers More common in women Most common subtype in nonsmokers Usually located peripherally Arises from bronchial mucosal glands More often have an elevated carcinoembryonic antigen (CEA) tumour marker Prognosis: 13% 5-year survival (cancer that does not reoccur in 5 years is generally less likely to reoccur over time comparatively) Squamous cell carcinoma Accounts for 20% of all lung cancers Most common in men Strongly associated with smoking Usually centrally located Characterized histologically by the presence of keratin pearls (whorl-shaped accumulations of keratin made by malignant squamous cells and are present in concentric layers in between the squamous epithelium) The type of lung cancer most often associated with hypercalcemia Prognosis: 14% 5-year survival Large cell carcinoma Accounts for 3% of all lung cancers Equally common in men & women Associated with smoking Typically manifests as a large peripheral mass This subtype is a diagnosis of exclusion Histologically, it has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (as seen in squamous cell carcinomas) or gland formation (as seen in adenocarcinomas) These cancers tend to grow and spread faster than adenocarcinomas or squamous cell carcinomas Prognosis: 10% 5-year survival Small Cell Lung Cancer Accounts for 13.8% of lung cancers Slightly more common in women Strongly associated with smoking Often located centrally or in the hilum Small cell lung cancers develop in the neuroendocrine cells of the lung These cancers grow and spread more quickly than non-small cell lung cancers Prognosis: 5% 5-year survival (These cell proliferate quickly, but mutate quickly and their initial sensitivity to chemo agents rapidly decreases in comparison to nonsmall cell cancers) Prognosis Tumor stage is the single most important predictor of prognosis The staging system for lung carcinoma uses the TNM scoring system T: tumor size and extent of local and/or regional spread in the lung and chest N: spread of tumor to regional or distant lymph nodes M: presence of distant metastases or involvement of the pleural fluid Staging (see the next slide for details) Stage I Small tumor size and absence of lymph node involvement and metastases Stages II & III Determined largely by the extent of regional lymph node involvement Stage IV Any tumor with distant metastasis Spread of Primary Lung Cancer At initial diagnosis 20% of patients have localized disease only 25% of patients have regional spread 55% of patients have distant spread (most of the reason for poor prognosis) Lung cancers metastasize most often to 1. Regional lymph nodes, particularly hilar and mediastinal nodes 2. Brain 3. Bone 4. Liver 5. Adrenal glands Clinical Features Lung cancer often does not produce any symptoms until the disease is quite advanced. In approximately 7-10% of cases, lung cancer is diagnosed in asymptomatic patients as an incidental finding on a chest x-ray performed for other reasons. Cough is reported to be the most common presenting symptom of lung cancer. The clinical signs and symptoms of lung cancers may be due to: The primary tumor itself Locoregional spread Distant metastatic disease Ectopic hormone production (paraneoplastic syndromes) Features Due to the Primary Tumour Central Tumours Peripheral Tumours Cough Hemoptysis Dyspnea Wheezing Atelectasis Severe pain due to infiltration of parietal pleura and the chest wall Pleural effusion Dyspnea Cough (collapse of prat or all of the lung) Postobstructive pneumonia (an infection of lung parenchyma secondary to bronchial obstruction) NB: Peripheral tumors are more likely to be discovered on routine chest radiographs or after they have become quite advanced Features of Pancoast Tumours These tumours may cause specific symptoms due to their location Shoulder and upper back pain are common as they often impact the ribs and/or spine Tumours involving the nerves of the brachial plexus can cause nerve entrapment syndromes: Horner’s syndrome: if the tumour impinges the sympathetic nerve plexus it can lead to Horner’s syndrome on the ipsilateral side: 1. Drooping of the upper eyelid (ptosis) 2. Constriction of the pupil (miosis) 3. Absence of sweating (anhidrosis) Pancoast syndrome: Severe arm and shoulder pain Pancoast tumours can extend to involve C8, T1, and T2 nerves, leading to shoulder pain or paresthesia that radiates down the arm in an ulnar distribution Atrophy of the small muscles of the hand Horner’s syndrome Features Due to Locoregional Spread Dyspnea, cough, edema of the face and/or upper extremity, venous distension, dysphagia, headache, all due to obstruction of the superior vena cava (superior vena cava syndrome) Hoarseness due to paralysis of the recurrent laryngeal nerve Elevated hemidiaphragm and worsening dyspnea due to phrenic nerve palsy Horner’s syndrome due to brachial nerve root compression Dysphagia due to esophageal compression Pericardial effusion Image reference: Wilson LD, Detterbeck FC, Yahalom J. Clinical practice. Superior vena cava syndrome with malignant causes. N Engl J Med. 2007 May 3;356(18):1862-9. doi: 10.1056/NEJMcp067190. Erratum in: N Engl J Med. 2008 Mar 6;358(10):1083. PMID: 17476012. Features of Distant Metastasis General Weight loss Cachexia (metabolic loss of muscle mass) Bone metastases Bone pain Spinal cord impingement Altered sensation Cramping or muscle weakness Difficulty urinating or incontinence Constipation Erectile dysfunction Paralysis Brain metastases Headache Altered mental status Seizure Ataxia Nausea and/or vomiting Liver metastases Hepatomegaly Anorexia Confusion Jaundice Nausea Adrenal gland metastases Adrenal insufficiency is uncommon Paraneoplastic Syndromes Clinical syndromes involving nonmetastatic systemic effects that accompany a cancer Collections of symptoms that result from substances produced by a cancer and occur remotely from the cancer itself, acting on other systems. Paraneoplastic syndromes associated with lung cancer can impair various organ functions and include neurologic, endocrine, dermatologic, rheumatologic, hematologic, and ophthalmological syndromes, as well as glomerulopathy and coagulopathy. Paraneoplastic syndromes may be the first signs of a cancer Paraneoplastic Syndromes There can be several causes of paraneoplastic syndromes, but the two most common causes are: The production and release of physiologically active substances by the cancer such as: hormones, hormone precursors, enzymes, or cytokines An altered immune response When a tumor arises, the body may produce antibodies to fight it which in some cases, can cross-react with normal tissues Paraneoplastic Syndromes Occur in 10% of people with primary lung cancers More common in small cell lung cancer but can also occur in nonsmall cell lung cancers The two most common examples are: Hypercalcemia due to ectopic production of a parathyroid hormone related peptide which occurs most commonly in patients with squamous cell carcinomas Syndrome of inappropriate antidiuretic hormone (SIADH) secretion which occurs mostly in small cell lung cancer Some other examples include: Digital clubbing and hypertrophic pulmonary osteoarthropathy and Trousseau’s syndrome of hypercoagulability which are caused more frequently by adenocarcinomas Cushing syndrome from ectopic adrenocorticotropic hormone (ACTH) production which occurs mostly in small cell lung cancer or carcinoid of the lung Table Reference: Karakas Y, Esin E, Lacin S, et al. A case of acanthosis nigricans as a paraneoplastic syndrome with squamous cell lung cancer. Onco Targets Ther. 2016 Aug 3;9:4815-20. doi: 10.2147/OTT.S95020. PMID: 27536145; PMCID: PMC4976921. Features of Paraneoplastic Syndromes Endocrine symptoms related to paraneoplastic syndromes usually resemble the typical endocrine disorders Hypercalcemia due to the production of PTH-related peptide by cancer cells presents like primary or secondary hyperparathyroidism with typical symptoms of hypercalcemia including thirst, muscle weakness, loss of appetite, confusion, abdominal pain, and depression Syndrome of inappropriate antidiuretic hormone (SIADH) secretion causes hyponatremia and presents with typical symptoms including thirst, muscle weakness, loss of appetite, confusion, abdominal pain, and depression Paraneoplastic Cushing syndrome is accompanied by hypokalemia, very high plasma ACTH levels, and increased serum and urine cortisol concentrations Pathogenesis of Primary Lung Cancers The risk of developing lung cancer depends on a combination of exposure to carcinogenic agents and an individual’s genetic susceptibility to these agents. 85-90% of lung cancers occur in tobacco smokers and the lifetime risk of developing lung cancer in smokers is 12-17% Occupational exposures to carcinogens account for approximately 10-15% of lung cancer cases. Exposure to Carcinogens Tobacco smoke Tobacco smoke contains more than 300 harmful substances with at least 40 known potent carcinogens Polyaromatic hydrocarbons and nicotine-derived nitrosamine ketone are known to cause DNA damage by forming DNA adducts in animal models Benzo-A-pyrine induces molecular signaling and mutations in p53 and other tumor suppressor genes Asbestos The most common occupational risk factor for lung cancer is exposure to asbestos Radon (indoors/homes) Radon exposure is associated with 10% of lung cancers Air pollution Outdoor air pollution accounts for 1-2% of lung cancers Genetic Susceptibility & Molecular Pathogenesis No single mutation determines the development of lung cancer, but some are common and may allow for targeted treatment with tyrosine kinase inhibitor therapy The most important abnormalities are mutations involving the ras family of oncogenes, particularly K-ras ras mutations are involved with the molecular pathogenesis of Non-small cell lung cancers and ras activation contributes to tumor progression and associated with a poor prognosis K-ras gene mutations occur in 25% of adenocarcinomas, 20% of large cell carcinomas, and 5% of squamous carcinomas, but rarely in small cell lung cancers K-ras mutations are correlates with cigarette smoking and with a poor prognosis in patients with adenocarcinoma. Currently there is no effective targeted molecular therapy available for K-ras mutations in lung cancer Genetic Susceptibility & Molecular Pathogenesis Epidermal Growth Factor Receptor (EGFR) Activating mutations in the tyrosine kinase domain of this gene are present in up to 25% of adenocarcinomas Mutations in the EGFR are more common in adenocarcinomas in nonsmokers, people of East Asian descent, and women. There are clinically important because these cancers respond very well to tyrosine kinase inhibitor drugs targeted against this receptor EML4-ALK Translocations Fusion between the genes for echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) occurs in 5% of adenocarcinomas Like EGFR mutations they are also most frequently in nonsmokers Brain metastases are common and present at diagnosis in 25% of these cases Adenocarcinomas with this mutation are also responsive to targeted tyrosine kinase inhibitor drugs EGFR and EML4-ALK mutations are mutually exclusive Genetic Susceptibility & Molecular Pathogenesis Other mutations associated with the development of primary lung cancers: ROS1 translocations: Fusions between ROS1 and a variety of fusions partners occur in 2% of all lung cancers MYC: Overexpression of this oncogene occurs in 10 – 40% of small cell lung cancers but is rare in other types TP53: Mutations in TP53 are identified in more than 80% of small cell and 50% of non–small cell lung cancers RB: Mutations in the retinoblastoma (RB) gene occur in >80% of small cell and 25% of non–small cell cancers Chromosome 3 (3p): Deletions in the short arm of this chromosome are frequently found in all types of lung cancers BCL2: This protooncogene encodes Bcl-2, a protein that inhibits apoptosis and is expressed in 25% of squamous cell carcinomas and 10% of adenocarcinomas PTEN: This tumor suppressor gene regulates cell survival signaling and is deficient in many non–small cell lung cancers Loss of PTEN is associated with poor prognosis and drug resistance. FGFR1 (fibroblast growth factor receptor 1): Amplification of FGFR1 is found in 20% of squamous cell carcinomas Early and extensive mutations in lung cancers result in pronounced intratumor heterogeneity by the time these cancers manifest clinically. This is thought to be why these cancers so often fail to respond to treatment. Carcinoid Carcinoid tumours most often appear in the gastrointestinal tract, but they can also start in the lung Lung carcinoid are very rare accounting for 2-3% of all lung cancers Develop in neuroendocrine cells of the normal bronchial epithelium Two subtypes: typical carcinoid and atypical carcinoid Equally common in men & women Not related to smoking Tend to grow slower than other types of lung cancers Although neuropeptides are readily demonstrated in the tumor cells, most do not cause endocrine paraneoplastic syndromes Prognosis: patients with Typical carcinoids have 90% 5-year survival after surgery (slow growing) Atypical carcinoids have 60% 5-year survival after surgery Mesothelioma Mesothelioma is a cancer of the pleural lining Rare, accounting for about 5% of all lung cancers This type of cancer is most often caused by asbestos exposure Develops over a long period time, 30 to 50 years between exposure to asbestos and diagnosis Patients first present with a pleural effusion or a pleural mass, chest pain, and nonspecific symptoms, such as weight loss and malaise Pleural mesotheliomas tend to spread locally within the chest cavity, invading and compressing major structures. Treatment is largely ineffective, and prognosis is poor. Few patients survive longer than 18 months after diagnosis. Metastasized Cancer The lungs are a common site of metastasis of other cancers via the lymphatic system or the bloodstream Cancers can spread to any location in the lungs, but most metastatic cancers develop near the edges of the lungs and in the lower lobes There can be a single metastasis in one lung or many metastases in one or both lungs Lung metastases may not cause any symptoms initially. The symptoms will vary depending on the number of tumours and their location in the lungs Almost any cancer can metastasize to the lung, but some are more common to do so, including: Bladder cancer Breast cancer Colorectal cancer Kidney cancer Melanoma Sarcomas Testicular