Carcinogenesis

Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure that prevent the normal process of cell division. Normal cells have programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death, but cancer cells proliferate without regulation. The genetic changes that cause cancer may occur in reproductive cells of the ova and sperm and propagate to progeny. Somatic changes are acquired during an individual’s lifetime because of exposure to carcinogenic chemicals, tobacco, radiation, and other factors. Mutations in oncogenes that promote cell growth and tumor suppressor genes that reduce cell growth are important mechanisms in the dysregulation of cell division and lead to cancer. Cancers are classified by their cell type and their location.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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DNA-Damaging Agents

Overview

  • Genetic mutations are considered the primary cause of cancer.
  • Numerous mutations are required.
  • Cell growth dysregulation → uncontrollable cell growth
  • > 1 in 3 cases of cancer are attributed to a modifiable risk factor (e.g., smoking)
  • Predispose to cancer:
    • Chemical exposure (including tobacco and alcohol)
    • Radiation exposure (sunlight, x-rays X-rays X-rays are high-energy particles of electromagnetic radiation used in the medical field for the generation of anatomical images. X-rays are projected through the body of a patient and onto a film, and this technique is called conventional or projectional radiography. X-rays)
    • Infections (e.g., human papillomavirus Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV)

Chemical carcinogens

  • Benzene and toluene: found in gasoline and cigarettes
  • Ethanol
  • Cigarettes (many carcinogenic chemicals)
  • Vinyl chloride
  • Nitrosamines: found in cured meats and smoked foods → gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
  • Asbestos: found in insulating materials:
    • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
    • Mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma
    • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
  • Arsenic:
    • Squamous cell cancer of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and lung
    • Angiosarcoma of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • Silica: associated with sandblasting → lung cancer
  • Chromium and nickel → lung cancer

Radiation

  • Nonionizing radiation:
    • Ultraviolet B (UVB) light → skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancer
    • Produces pyrimidine dimers in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure leading to transcriptional errors; also, mutations of oncogenes and tumor suppressor genes
  • Ionizing radiation:
    •  X-rays: associated with hematologic malignancies
    • Atomic bomb → leukemias, thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
    • Uranium → lung cancer
    • Radium → osteosarcoma Osteosarcoma Osteosarcoma is a primary malignant tumor of the bone characterized by the production of osteoid or immature bone by the tumor cells. The disease is most common in children and young adults and most frequently affects growth plates of the long bones, although it can involve any bone. Osteosarcoma
    • Gamma rays:
      • Considered the most dangerous form of ionizing radiation
      • Can affect tissue from the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin to deep structures like bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
    • Alpha particles in radon gas → lung cancer

Infections

  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure viruses: 
    • Human papillomavirus: cervical carcinoma 
    • Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus: infects B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and epithelial cells of nasopharynx via CD21 
      • Burkitt lymphoma 
      • B-cell lymphoma
      • Hodgkin disease
      • Nasopharyngeal carcinomas
    • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus: hepatocellular ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver) carcinoma
  • RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure viruses: 
    • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus: hepatocellular ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver) cancer 
    • Human T-cell leukemia virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview type 1: infects CD4+ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells to produce T-cell leukemia/lymphoma
  • Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview: Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori
    • Linked to gastric carcinomas and lymphomas (B cell)
    • Can be reversed with triple-therapy treatment before developing into lymphoma
Mechanisms of carcinogenesis due to carcinogens causing dna damage

Mechanisms of carcinogenesis due to carcinogens causing DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage

Image by Lecturio. License: CC BY-NC-SA 4.0

Pathogenesis

Overview

  • Cancer is a problem with cellular dysfunction; it does not have to be lethal genetic damage.
  • Occurs in a multistep process: exposure to carcinogen → genes involved in cell growth, differentiation, and survival activated
  • Carcinogens lead to the development of mutations that are passed along to future generations of cells.
  • These mutations lead to faster cell proliferation, further mutations, and eventually, metastasis (spread of cancer to other locations of the body via the hematologic or lymphatic system).

Cellular changes

  • Gradual changes in cell properties accumulate with genetic changes that occur over a long period of time.
  • Clonal expansion of a single genetically damaged precursor cell → tumor
  • Typical cellular changes that accompany the development of cancer:
    • Hyperplasia (increase in the number of cells)
    • Increasing variation in cell and nuclear size and shape
    • Loss of tissue structure
  • Dysplasia: abnormal proliferation with loss of normal structure of cells 
    • Severe dysplasia: carcinoma in situ
    • Carcinoma in situ describes a state in which there are dysplastic cells that have not migrated or invaded other tissue.
  • The transformation from a normal cell to a cancer cell requires many steps that prove advantageous to growth:
    • Self-sufficiency in growth signaling
    • Insensitivity to anti–growth signaling
    • Evade apoptosis
    • Limitless replicative potential
    • Sustained angiogenesis
    • Tissue invasion and potential for metastasis
Pathophysiology of cancer carcinogenesis

Pathophysiology of cancer

Image: “Mechanisms contributing to evasion of apoptosis and carcinogenesis” by Wong, R.S. License: CC BY 2.0

Regulatory Genes

There are 4 classes of normal regulatory genes that are often damaged.

  • Oncogenes (e.g., c-myc in Burkitt lymphoma):
    • Promote cell growth and division
    • Increased expression → carcinogenesis (uncontrolled cell growth)
    • Allow for cells to avoid programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death (apoptosis)
    • Categorized according to their cellular function:
      • Growth factor: leads to cell proliferation
      • Tyrosine kinase: passes along cell signals
      • Guanosine triphosphatase (GTPase): passes along cell signals
      • Transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription factor: induces cell growth and division
    • Proto-oncogene: nonfunctional version of an oncogene:
      • Up-regulation (a type of mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations that increases expression) in a proto-oncogene allows for the gene to become an oncogene.
      • With this mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, an oncogene promotes cell growth.
  • Tumor suppressor genes: 
    • Inhibit cell division
    • Decreased expression → carcinogenesis
    • Normally function to prevent uncontrolled cell growth
    • Mutation → uncontrolled cell growth
    • Tumor suppressor genes are categorized:
      • Caretaker gene: involved in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair
      • Gatekeeper gene: regulate cell growth
  • Genes that regulate apoptosis:
    • Significant mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations → no programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death 
    • Mutations are passed along to future cell lines.
    • p53 is a tumor suppressor gene that promotes apoptosis when it is functioning normally
      • After loss-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, p53 does not arrest the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle
      • p53 is implicated in nearly half of all known cancers.
  • Genes involved in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair

Cancer Subtypes

Type of cell

  • Carcinoma: derived from epithelial cells 
  • Sarcoma: derived from connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
  • Lymphoma and leukemia: derived from bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
  • Germ cell tumor: derived from pluripotent cells

Common cancers

  • Osteosarcoma: bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones cancer of mesenchymal origin
  • Glioblastoma: aggressive brain cancer
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or nonheritable. Retinoblastoma: intraocular cancer arising from the retina
  • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
  • Pancreatic cancer
  • Prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
  • Hematopoietic cancer:
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia 
    • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia 
    • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cancer arising from melanocytes
  • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer:
    • Small-cell lung cancer
    • Non–small-cell lung cancer:
      • Adenocarcinoma
      • Squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma

Clinical Relevance

  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer: 2nd most common cause of cancer-related death in women after lung cancer. The most common histologic type of breast cancer is infiltrating ductal carcinoma. Screening with mammography is recommended, and diagnosis is made by biopsy. Treatment relies on surgery, radiation, and systemic therapies (e.g., chemotherapy, endocrine therapy).
  • Prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer: most common cancer in men. Most often, prostate cancer is slow-growing, and for this reason, there is disagreement about the need for routine screening. Risk factors are older age, African American or Caribbean heritage, and family history of prostate cancer. The preferred method for screening is PSA testing. Diagnosis is confirmed with biopsy. 
  • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer: Bronchogenic carcinoma, or lung cancer, is a malignancy that arises from the epithelial lining of the bronchus or bronchiole. Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer is the most common cancer death in the United States. Tobacco smoking is the most important risk factor for disease, and smoking cessation decreases the risk of lung cancer. A patient may present with cough, weight loss, hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis, or chest discomfort. Chest CT is used for screening in patients with an extensive smoking history. Diagnosis is with biopsy. Treatment may involve surgery, radiation, and chemotherapy.

References

  1. Botelho, M.C., et al. (2014). Carcinogenesis. In Wexler, P. Ed., Encyclopedia of Toxicology, 3rd ed.
    Elsevier, pp. 713–729. https://www.sciencedirect.com/science/article/pii/B9780123864543003717
  2. National Cancer Institute: National Institutes of Health. (2021). What is cancer? Retrieved May 6, 2021, from https://www.cancer.gov/about-cancer/understanding/what-is-cancer 
  3. Dunn, L., Rudin, C.M. (2021). Head and neck squamous cell carcinogenesis: molecular and genetic alterations. UpToDate. Retrieved July 20, 2021, from https://www.uptodate.com/contents/head-and-neck-squamous-cell-carcinogenesis-molecular-and-genetic-alterations
  4. Frucht, H., Lucas, A.L. (2021). Molecular genetics of colorectal cancer. UpToDate. Retrieved July 20, 2021, from https://www.uptodate.com/contents/molecular-genetics-of-colorectal-cancer

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