Lung Cancer PDF

# Lung Cancer Roughly 95% of primary lung tumors are carcinomas. The remaining 5% span a miscellaneous group: carcinoid, mesenchymal malignancies, lymphomas, and benign lesions. The most common benign tumor is "hamartoma". ## Carcinoma Carcinoma of the lung is strongly associated with tobacco sm...

# Lung Cancer Roughly 95% of primary lung tumors are carcinomas. The remaining 5% span a miscellaneous group: carcinoid, mesenchymal malignancies, lymphomas, and benign lesions. The most common benign tumor is "hamartoma". ## Carcinoma Carcinoma of the lung is strongly associated with tobacco smoking and is the leading cause of cancer-related death in high-resource countries. It has long held this position among males in the United States, accounting for about one-third of cancer deaths in men, and since 1987 has been the leading cause of cancer deaths in women. - Over 50% of patients with lung cancer at diagnosis already have distant metastases. - Another 25% have disease in the regional lymph nodes. - The overall prognosis remains very poor. - The 5-year survival rate for all stages of lung cancer is about 20%. ### Histologic types of Lung Carcinoma - The four major histologic types of lung carcinoma are: - adenocarcinoma - squamous cell carcinoma - small cell carcinoma - large cell carcinoma - There is a combination of histologic patterns, for example, small cell carcinoma and adenocarcinoma. - Squamous cell and small cell carcinoma have the strongest association with smoking. - Adenocarcinoma has replaced squamous cell carcinoma as the most common primary lung tumor in recent years. - Adenocarcinoma is also the most common primary lung tumor in women, never-smokers, and individuals younger than 45 years of age. ### Classification of Lung Carcinoma - **Historically, lung carcinoma was classified into two broad groups:** - small cell lung cancer (SCLC) - nonsmall cell lung cancer (NSCLC) - NSCLC includes: - adenocarcinoma - squamous cell carcinoma - large cell carcinoma ### Pathogenesis - **Lung cancer arises by a stepwise accumulation of driver mutations that produce neoplastic cells possessing the hallmarks of cancer.** - **The order of molecular changes is not random but tends to follow an order that parallels the histologic progression toward cancer:** - Inactivation of one or more putative tumor suppressor genes located on the short arm of chromosome 3 (3p) is a very common early event. - Mutations in the TP53 tumor suppressor gene and the KRAS oncogene occur relatively late. - **Certain genetic changes are found even in benign bronchial epithelium of people who smoke but do not have lung cancer, suggesting that large areas of the respiratory mucosa are mutagenized by exposure to carcinogens ("field effect").** - **Cells that accumulate additional mutations ultimately develop into cancer.** ### **Adenocarcinoma** - A subset of adenocarcinomas, particularly those arising in nonsmoking women, harbor mutations that activate the epidermal growth factor receptor (EGFR). - The frequency of this mutation varies in different populations. - These tumors are sensitive to drugs that inhibit EGFR signaling, although the response is often short lived. ### **Environmental Carcinogens** - Cigarette smoking is the main culprit responsible for the mutations that give rise to lung cancers. - About 90% of lung cancers occur in individuals who are currently smoking or who have stopped recently. - There is a nearly linear correlation between the frequency of lung cancer and pack-years of cigarette smoking. - The increased risk is 60 times greater among individuals who smoke heavily (two packs a day for 20 years) than among nonsmokers. - Women are more susceptible to carcinogens in tobacco smoke than men. - Cessation of smoking decreases the risk for developing lung cancer over time, but it never returns to baseline levels. - Genetic changes that predate the full development of lung cancer can persist for many years in the bronchial epithelium of people who formerly smoked. - Passive smoking (proximity to people who are smoking cigarettes) also increases the risk for developing lung cancer, as does smoking of pipes and cigars. ### **Other Carcinogenic Influences** - Other carcinogenic influences associated with occupational exposures act in concert with smoking and may sometimes be solely responsible for lung cancer. - Examples include: - work in uranium mines - work with asbestos - inhalation of dusts containing arsenic, chromium, nickel, or vinyl chloride. - **A cardinal example of a synergistic interaction between two carcinogens is found in asbestos and tobacco smoking. ** - Exposure to asbestos in nonsmokers increases the risk for developing lung cancer 5-fold. - Exposure to asbestos in individuals who smoke heavily is elevated approximately 55-fold. ### **Genetic Factors** - Even though smoking and other environmental influences are paramount in the causation of lung cancer, not all individuals exposed to tobacco smoke develop cancer. - It is very likely that the mutagenic effect of carcinogens is modified by genetic factors. - Individuals with certain polymorphisms involving the P-450 genes have an increased capacity to activate procarcinogens found in cigarette smoke and are thus exposed to larger doses of these carcinogens. - Individuals whose peripheral blood lymphocytes undergo chromosomal breakages after exposure to tobacco-related carcinogens have a greater than 10-fold increased risk for developing lung cancer over control subjects. ### **Adenoma-Carcinoma Sequence** - By analogy to the adenoma-carcinoma sequence in the colon, it is proposed that some invasive adenocarcinomas of the lung arise through an atypical adenomatous hyperplasia-adenocarcinoma in situ-invasive adenocarcinoma sequence. - Studies of lung injury models in mice have identified a population of multipotent cells in the lung periphery at the bronchioloalveolar duct junction, termed bronchioalveolar stem cells (BASCs). - After lung injury, multipotent BASCs proliferate and replenish the normal cell types (bronchiolar Clara cells and alveolar cells) found in this location, thereby facilitating epithelial regeneration. - It is postulated that BASCs incur the first mutation that initiates the changes that develop in full-blown malignancy. ### **Squamous Cell Carcinoma** - The sequential morphologic changes leading to development of squamous cell carcinomas are well documented. - There is a linear correlation between the intensity of exposure to cigarette smoke and the appearance of ever more worrisome epithelial changes that begin with rather innocuous basal cell hyperplasia and squamous metaplasia and progress to squamous dysplasia and carcinoma in situ, before culminating in invasive cancer. ### **Small Cell Carcinoma** - Precursor lesions for small cell carcinoma have not been clearly described. - These tumors are also distinct from other forms of lung carcinoma in virtually always having loss of function mutations in both TP53 and RB. - Small cell carcinoma is marked by high growth rates and early development of widespread metastases. ## Table: Comparison of Small Cell Lung Cancer and Non-small Cell Lung Cancer | Feature | Small cell lung cancer | Non-small cell lung cancer (Adenocarcinoma and Squamous cell carcinoma) | |---|---|---| | Morphology | Scant cytoplasm, small, hyperchromatic nuclei with fine chromatin pattern; indistinct nucleoli; diffuse sheets of cells | Abundant cytoplasm, pleomorphic nuclei with coarse chromatin pattern; prominent nucleoli; glandular or squamous architecture | | Neuroendocrine Markers | Present | Absent | | Dense core granules on electron microscopy; expression of chromogranin, synaptophysin, and CD56 | Present | | | Epithelial Markers | Present | Present| | Epithelial membrane antigen, carcinoembryonic antigen, and cytokeratin intermediate filaments | | | | Mucin | Absent | Present in adenocarcinomas | | Peptide hormone production | Adrenocorticotropic hormone, anti-diuretic hormone, gastrin-releasing peptide, calcitonin | Parathyroid hormone-related peptide (PTH-rp in squamous cell carcinoma) | | Tumor Suppressor Gene Abnormalities | | | | 3p deletions | >90% | >80% | | RB mutations | >90% | ~20% | | p16/CDKN2A mutations | ~10% | >50% | | TP53 mutations | >90% | >50% | | Dominant Oncogene Abnormalities | | | | KRAS mutations | Rare | >30% (adenocarcinomas) | | EGFR mutations | Absent | ~20% (adenocarcinomas, nonsmokers, women) | | ALK rearrangements | Absent | 4%-6% adenocarcinomas, nonsmokers, often have signet ring morphology | | Response to Therapy | | | | Response to chemotherapy and radiotherapy | Often complete response but invariably recur | Incomplete | | Response to checkpoint inhibitor therapy | Unresponsive | Responsive | ## Small Cell Lung Carcinoma - Small cell carcinoma generally appears as a pale gray, centrally located mass that extends into the lung parenchyma. - The tumor cells are relatively small and round to fusiform in shape and have scant cytoplasm and finely granular chromatin with a salt-and-pepper appearance. - Numerous mitotic figures are present, as is necrosis, which may be extensive. - The tumor cells are fragile and often show fragmentation and "crush artifact" in small biopsy specimens, releasing DNA that stains blue (Azzapardi effect). - These tumors express a variety of neuroendocrine markers and may secrete polypeptide hormones that may result in paraneoplastic syndromes. - By the time of diagnosis, most have metastasized to hilar and mediastinal lymph nodes. ## Non-small Cell Lung Carcinoma - Adenocarcinoma is usually peripherally located but may also occur closer to the hilum. - In general, adenocarcinoma grows more slowly and forms smaller masses than do the other subtypes but also tends to metastasize widely at an early stage. - It may assume a variety of growth patterns, including acinar (gland-forming), papillary, mucinous, or solid types. - Squamous cell carcinoma is more common in men than in women and is closely correlated with a smoking history. - It tends to arise centrally in major bronchi and to spread first to local hilar nodes. - Large lesions may undergo central necrosis, giving rise to cavitation. ## Carcinoid Tumors - Carcinoid tumors are malignant tumors composed of cells that contain dense-core neurosecretory granules in their cytoplasm and occasionally secrete hormonally active polypeptides. - They are best thought of as a low-grade neuroendocrine carcinoma and are sub-classified as typical or atypical; both are often resectable and curable. - They may occur as part of the multiple endocrine neoplasia syndrome. - Bronchial carcinoids tend to occur in younger adults (mean 40 years) and represent about 5% of all pulmonary neoplasms. ## Nasopharyngeal Carcinoma - Nasopharyngeal carcinoma is a rare neoplasm that merits comment because of its strong epidemiologic links to EBV and its high frequency in certain populations, particularly Southern China. - It is thought that EBV has the capacity to infect nasopharyngeal epithelium and that, in some susceptible individuals, this leads to transformation of the epithelial cells. ### Types of Nasopharyngeal Carcinoma - Nasopharyngeal carcinoma has three histologic variants: - keratinizing squamous cell carcinoma. - nonkeratinizing squamous cell carcinoma, - undifferentiated carcinoma. - The last-mentioned is the most common and the one most closely linked with EBV. - The tumor cells contain EBV genomes and express several EBV proteins, including latent membrane protein-1 (LMP1), which generates oncogenic signals that active the NF-KB pathway. ## Laryngeal Tumors - A variety of nonneoplastic, benign and malignant neoplasms of epithelial and mesenchymal origin may arise in the larynx, but only vocal cord nodules, papillomas, and squamous cell carcinomas are sufficiently common to merit comment. - The most common presenting feature is hoarseness. ### Nonmalignant lesions - Vocal cord nodules ("polyps") are smooth, hemispherical protrusions that are most often located on the true vocal cords. - The nodules are composed of fibrous tissue and covered by stratified squamous mucosa that is usually intact but may be ulcerated from trauma caused by contact with the other vocal cord. - These lesions occur chiefly in individuals who smoke heavily or singers (singer's nodes), suggesting that they are the result of chronic irritation or overuse. ### Laryngeal Papilloma - Laryngeal papilloma or squamous papilloma of the larynx is a benign neoplasm, usually located on the true vocal cords, that forms a soft, raspberry-like excrescence rarely more than 1 cm in diameter. - Histologically, it consists of multiple slender, fingerlike projections supported by central fibrovascular cores and covered by an orderly stratified squamous epithelium. - When the papilloma is on the free edge of the vocal cord, trauma may lead to ulceration that can be accompanied by hemoptysis. ### Papillomas - Papillomas are usually single in adults but are often multiple in children. - These lesions are referred to as recurrent respiratory papillomatosis due to the tendency to recur after excision. - These lesions are caused by human papillomavirus (HPV) types 6 and 11 and often spontaneously regress at puberty. - Cancerous transformation is rare. - The most likely cause for their occurrence in children is vertical transmission from an infected mother during delivery. - The recent availability of an HPV vaccine can protect women of reproductive age against infection with types 6 and 11 and provides an opportunity for prevention of laryngeal papillomatosis in children. ## Carcinoma of the Larynx - Carcinoma of the larynx represents only 2% of all cancers. - It most commonly occurs after 40 years of age and is more common in men than in women (M: F ratio of 7:1). - Environmental factors are very important in its causation: nearly all cases occur in people who smoke. - Alcohol and asbestos exposure may also have roles. - Human papillomavirus sequences have been detected in about 15% of tumors, which tend to have a better prognosis than other carcinomas. ### Types of laryngeal carcinoma - About 95% of laryngeal cancers are squamous cell carcinomas. - Rarely, adenocarcinomas are seen. - The tumor develops directly on the vocal cords (glottic tumors) in 60% to 75% of cases or may arise above the cords (supraglottic; 25% to 40%) or below the cords (subglottic; <5%). - Laryngeal squamous cell carcinoma appears as a pearly gray, wrinkled plaque that undergoes ulceration and can fungate with tumor progression. - The glottic tumors are usually keratinizing, well to moderately differentiated squamous cell carcinomas. ## Carcinoma of the larynx - Carcinoma of the larynx usually presents with persistent hoarseness. - The location of the tumor within the larynx has a significant bearing on prognosis. - About 90% of glottic tumors are confined to the larynx at diagnosis because these tumors interfere with vocal cord mobility and cause symptoms early in their course and also because the glottic region has a sparse lymphatic supply, making spread less likely. - By contrast, the supraglottic larynx is rich in lymphatics and nearly one-third of supraglottic tumors metastasize to regional (cervical) lymph nodes. - Subglottic tumors have the worst prognosis because they tend to produce few symptoms until they are advanced. - With surgery, radiation therapy, or combination treatment, many patients can be cured. - About one-third die of the disease. - The usual cause of death is widespread metastases and cachexia, sometimes complicated by pulmonary infection.