Summary![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Oncology is the science of tumors. This article explains basic concepts relevant to the development, progression, spread, and diagnosis of cancer. Histological analysis helps to determine tumor type and grade, whereas the TNM classification system is used to assess staging. Because it is standardized and used internationally, the TNM classification helps unify oncological research and therapy protocols. Metastasis occurs via different pathways mainly by hematogenous or lymphatic spreading.
Principles of cancer care, paraneoplastic syndromes, and tumor markers are covered in detail in their respective articles.
Nomenclature![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Terminology
Basic terminology in oncology | |
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Term | Definition |
Normal cell |
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Neoplasia |
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Tumor | |
Adenoma |
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Carcinoma |
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Sarcoma |
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Hamartoma |
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Choristoma |
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Dysplasia |
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Carcinoma in situ (CIS) |
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Invasive carcinoma |
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Metastasis |
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Benign and malignant tumors
Overview of benign and malignant tumors | ||
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Benign tumor | Malignant tumor | |
Differentiation (grading) |
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Growth | ||
Macroscopy |
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Microscopy |
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Metastasis and relapse |
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Tumor origin
Types of tumors based on cell origin | |||
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Type of tumors | Cell origin | Benign tumor | Malignant tumor |
Epithelial tumors |
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Mesenchymal tumors |
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Special variants of mesenchymal tumors |
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Neuroectodermal tumors |
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Germ cell tumors |
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Embryonal tumors |
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General epidemiology![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
In 2020, approximately 1.8 million people will be diagnosed with cancer in the United States. Cancer is the 2nd leading cause of death; after heart disease. The most common type of cancer in both men and women is skin cancer, with basal cell carcinoma being more common than squamous cell carcinoma and melanoma. [1]
Epidemiology of common cancer types in 2020 [2]
The following numbers are an estimation of new cancer cases and their mortality in the United States (excluding skin cancer ).
Epidemiology of most common cancer types | |||
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Type | Incidence/year in men | Incidence/year in women | Mortality/year |
Breast cancer | 2,620 | 276,480 | 42,690 |
Lung and bronchus cancer | 116,300 | 112,520 | 135,720 |
Prostate cancer | 191,930 | N/A | 33,330 |
Colorectal cancer | 78,300 | 69,650 | 53,200 |
Bladder cancer | 62,100 | 19,300 | 17,980 |
Kidney cancer | 45,520 | 28,230 | 14,830 |
Uterine cancer | N/A | 65,620 | 12,590 |
Pancreatic cancer | 30,400 | 27,200 | 47,050 |
Thyroid cancer | 12,720 | 40,170 | 2,180 |
Non-Hodgkin lymphoma | 42,380 | 34,860 | 19,940 |
Leukemia | 35,470 | 25,060 | 23,100 |
- The most common types of cancer in men (excluding skin cancer)
- The most common cancer in women (excluding skin cancer)
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The types of cancer with the highest mortality rate in both men and women (in descending order)
- Cancer of lung and bronchus
- Prostate cancer (men), breast cancer (women)
- Colorectal cancer
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The most common types of cancer that have the greatest mortality rate in children (< 15 years)
- Leukemia (ALL, AML)
- Brain and spinal cord tumors
- Neuroblastoma
Carcinogenesis![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Overview
- Definition: a multistep process by which normal cells develop and accumulate genetic mutations (inherited or acquired), resulting in a monoclonal expansion of mutated cells that can progress to the development of neoplasia
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Process
- Initiation: DNA damage
- Promotion: DNA damage passed on
- Latency: the time between promotion and progression
- Progression: proliferation of the neoplastic cell line with the acquired DNA damage, leading to malignant transformation
Properties of malignant cells
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Sustained proliferative signaling: due to mutation of genes regulating cell division and growth
- (Proto‑)oncogene: See “Proto-oncogene” below.
- Growth factor receptors; (e.g., HER2/neu, EGFR)
- Signaling molecules; (e.g., Ras, B-Raf) [3]
- Transcription factors; (e.g., MYC, TP53) [4]
- Cell cycle regulators; (e.g., cyclins, CDKs)
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Evade growth suppressors [5]
- Tumor suppressor genes: See “Tumor suppressor genes” below.
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Loss of contact inhibition
- Mutated or absent E-cadherin → loss of growth inhibitory signals and contact inhibition of proliferation → excessive cell proliferation
- Due to mutations in genes that regulate contact inhibition (e.g., NF2 gene)
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Genome instability and mutations
- Mutations: See “Gene mutations” and “Chromosomal translocation” in the “Basics of human genetics” article.
- Gene amplification; : increased gene expression (e.g., overexpression of HER2/neu gene in several forms of breast cancer)
- Resist cell death
- Enable replicative immortality: telomerase reactivation → ↑ length of telomeres → ↑ number of possible cell replication cycles
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Deregulate cellular energetics: a shift in cellular metabolism from glycolysis and mitochondrial oxidative phosphorylation to glycolysis and preferential lactate generation, regardless of the oxygen supply (Warburg effect)
- In differentiated, non-malignant cells, glycolysis converts glucose to pyruvate, which then undergoes mitochondrial oxidative phosphorylation under aerobic conditions, or anaerobic glycolysis to generate lactate under anaerobic conditions.
- In malignant cells, the so-called Warburg effect occurs, in which pyruvate is preferentially converted to lactate, regardless of the cellular oxygen supply. This mechanism supplies rapidly dividing malignant cells with the necessary carbon to synthesize cellular structures. [6]
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Induce angiogenesis [5]
- Angiogenesis helps maintain an adequate supply of oxygen and nutrients to the neoplastic cells.
- Regulated by angiogenic (e.g., VEGF, FGF) and inhibitory factors that are produced by neoplastic or supporting cells
- Occurs as:
- Vasculogenesis: de novo formation of blood vessels from bone marrow-derived endothelial cells
- Neoangiogenesis: formation of blood vessels from existing blood vessels and capillaries
- Newly formed blood vessels may be dilated or leaky.
- Activate invasion and metastasis: See “Metastasis” below.
- Avoid immune detection: See “Defense mechanisms of malignant cells” below.
- Tumor-promoted inflammation
Defense mechanisms of malignant cells [7]
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Immune response modification
- ↓ MHC class I expression on malignant cells → inability of cytotoxic T-cells to recognize and mount an immune response against these cells
- Secretion of immunosuppressive molecules (e.g., TGF-β) → enhanced immune tolerance of malignant cells
- Enhanced regulatory T-cell activity → limited immune response
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Immune checkpoints [8]
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Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
- Upregulation of CTLA-4 → promotion of binding to B7 protein (surface receptor on antigen-presenting cells, also called CD80 or CD86) → T-cell inactivation and simultaneous reduction of costimulation by binding of CD28 to B7
- CTLA-4 is inhibited by anti-CTLA-4 antibody ipilimumab.
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Programmed death-ligand system
- Expression of programmed death-ligand 1 (PD-L1) and PD-L2 on tumor cells surface or environment → binding to programmed cell death protein 1 (PD-1) on T-cells → T-cell dysfunction
- PD-L1 and PD-L2 are inhibited by cancer immunotherapy agents atezolizumab, durvalumab, and avelumab.
- PD-1 is inhibited by cancer immunotherapy agents nivolumab and pembrolizumab.
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Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
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Development of resistance to chemotherapeutic agents
- Expression of multidrug resistance protein 1 (MDR1; also called P-glycoprotein). [9]
- P-glycoproteins are transmembrane ATP-dependent efflux pump proteins that decrease intracellular concentrations of chemotherapeutics.
- Expressed in adrenocortical carcinoma as well as cancers of the colon, liver, pancreas, kidney, ovary, and breast
Oncogene![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
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Oncogene: the product of a gain-of-function mutation in a proto-oncogene which leads to overexpression of signaling proteins and growth factors, and thus, uncontrolled cellular proliferation (e.g., dysplasia, neoplasia)
- Only one allele of the proto-oncogene requires damage to form an oncogene.
- Often present in cancer cells
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Proto-oncogene: Genes that encode proteins that are important in normal cell division and cell differentiation. Examples include:
- Protein kinases, e.g., protein kinase B (PKB)
- PKB activates and inhibits various substrates, regulates apoptosis, activates translation and, indirectly, cell division.
- PKB is activated by phosphatidylinositide 3-kinase (PI3K).
- Ligand-directed transcription factors (intracellular hormone receptors)
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GTP-binding proteins
- G protein-coupled receptors
- Small G-proteins such as Ras
- Tyrosine kinase receptors
- Growth factors and cytokines
- Protein kinases, e.g., protein kinase B (PKB)
Overview of proto-oncogenes [10] | |||
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Proto-oncogene | Chromosome | Gene product | Associated malignancies |
BRAF |
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BCR-ABL |
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JAK2 |
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ALK |
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RET |
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c-KIT |
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L-myc-1 (MYCL1) |
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N-myc (MYCN) |
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c-myc |
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KRAS |
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BCL-2 |
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CDK4 |
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CCND1 |
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ERBB1 |
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“Adenocarcinoma of Lung Kinase”: Cancer (adenocarcinoma of lung) and the gene product (tyrosine kinase) are associated with ALK mutations.
L-myc is associated with lung cancer and n-myc with neuroblastoma.
c-KIT mutations affect CytoKIne recepTor production.
BCL-2 mutations are associated with diffuse large B-cell lymphoma.
Tumor suppressor genes![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
- Tumor suppressor gene: a gene that normally controls and suppresses cell proliferation
Overview of tumor suppressor genes | |||
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Gene | Chromosome | Gene product | Associated malignancy |
TP53 |
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Rb |
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CDKN2A |
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APC gene |
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PTEN [13] |
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BRCA1 |
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BRCA2 |
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MMR gene family |
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DCC (Deleted in colorectal cancer) |
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SMAD4 (DPC4) (Deleted in pancreatic cancer) |
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MEN 1 |
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NF1 |
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NF2 |
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TSC1 (Tuberous sclerosis complex 1) |
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TSC2 (Tuberous sclerosis complex 2) |
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VHL |
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WT1 (Wilms Tumor 1) |
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WT2 (Wilms Tumor 2) |
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Mutations of the Rb (retinoblastoma) gene mutations cause Retinoblastomas and bone cancer (osteosarcoma).
PTEN mutation is associated with cancers of the Prostate, breasT, and ENdometrium.
Mutations in MEN 1 affect its gene product: MENin.
Carcinogens![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Chemical carcinogens
Examples of chemical carcinogens | ||
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Substance | Sources of exposure | Malignancy |
Aflatoxin |
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Alkylating agents | ||
Aromatic amines (β-naphthylamine, benzidine) |
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Arsenic |
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Asbestos |
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Benzene, benzol |
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Beryllium |
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Chromium |
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Cigarette smoke |
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Ethanol |
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Nickel |
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Nitrosamines |
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Radon |
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Silica |
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Wood dust |
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Radiation
Overview of radiation | ||
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Type | Occurrence | Malignancy |
Nonionizing radiation |
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Ionizing radiation |
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Oncogenic infections
Infective agent | Associated malignancies |
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DNA viruses | |
EBV | |
HBV | |
HHV-8 | |
HPV 16 | |
HPV 18 | |
RNA viruses | |
HTLV-1 | |
HCV | |
Nonviral pathogens | |
Schistosoma haematobium |
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Clonorchis sinensis (Chinese liver fluke) | |
H. pylori | |
Streptococcus bovis |
Cancer-Immunity cycle![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Grading and staging![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Tumor grading
- Definition: the process of classifying tumors based on their histological appearance (degree of cell differentiation)
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Indicators of poor differentiation
- High-proliferation index
- Presence of nucleoli
- Giant cells with multiple nuclei
- Hyperchromasia and heterogeneous chromatin distribution
- Abnormal shape of cell or nucleus (nuclear atypia, enlarged nucleoli)
- Different cell polarity
- Different orientation of nuclei belonging to the same group of cells
- Increase in mitotic figures
- Anaplasia: loss of morphological features of malignant cells so that resemblance to normal cells of a particular tissue where tumor cell originated from is lost
Grading systems
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AJCC grading system
- Most commonly used grading system for nonhematological malignancies
- Can be applied to a wide range of tumors
- Usually, higher-grade tumors are more aggressive than lower-grade tumors.
Grading | Differentiation of malignant tissue |
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G1 | Well differentiated (low grade) |
G2 | Moderately differentiated (intermediate grade) |
G3 | Poorly differentiated (high grade) |
G4 | Undifferentiated/anaplastic (high grade) |
GX | Differentiation cannot be assessed. |
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Cancer-specific grading systems
- Gleason score for prostate cancer
- Nottingham grading system for breast cancer
Tumor staging [19]
- Definition: a method of determining and classifying a tumor according to its spread throughout the body
- Prognosis: The stage of the tumor is typically more important than the grade in determining the prognosis.
Spread determines Stage, and Stage determines Survival more than grade.
TNM classification
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T stage: size or direct extent of the primary tumor
- Tcis: carcinoma in situ (no basement membrane penetration and no infiltration of submucosa)
- T1–4 based on the size and/or extent of the primary tumor (T4 refers to the infiltration of neighboring organs)
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N stage: involvement of regional lymph nodes
- N0: no lymph node involvement
- N1–3 based on type of tumor and lymph node involvement
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M stage: presence of distant metastasis
- M0: no distant metastasis
- M1: present distant metastasis
- Mx: unknown if distant metastasis present or not
- By adding a "C" to any category, it is possible to express the certainty of the diagnosis:
- By adding a prefix to TNM it is possible to indicate additional diagnostic or clinical information:
- cTNM: staging based on clinical criteria
- pTNM: histopathological staging
T, N, and M have independent prognostic values. N and M are typically the most important determinants of prognosis.
AJCC staging system
- Stage 0 (carcinoma-in-situ)
- Stage I–III: Tumor spread into nearby tissues.
- Stage IV: Tumor spread to distant parts of the body.
Cancer-specific staging systems
Metastasis![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Definition
- Metastasis: the spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)
Types of metastasis [20]
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Lymphatic metastasis
- Dissemination of malignant cells via lymphatic vessels and lymph nodes
- Most common route of metastasis for most carcinomas
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Hematogenous metastasis
- Dissemination of malignant cells via blood vessels
- Venous dissemination is more common than arterial dissemination because thin vein walls facilitate invasion.
- Most common route of metastasis for most sarcomas
- Seeding (oncology): spillage of malignant cells to neighboring structures → implants at a site adjacent to the primary tumor and subsequent growth (e.g., after a biopsy of cancer the cancer cells spill and implant along the biopsy canal)
- Transcoelomic metastasis: spread of malignant cells into body cavities by penetration of surfaces such as the pleura, pericardium, and peritoneum (e.g., ovarian cancer spread to the liver via the peritoneal cavity)
- Canalicular metastasis: spread of malignant cells via canalicular system (e.g. bile ducts, lactiferous ducts, urinary tract, and the subarachnoid space)
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Cavitating pulmonary metastasis [21][22]
- Spread of malignant cells that form cavitary lesions in the lungs (e.g., gastrointestinal adenocarcinomas, renal cell carcinoma)
- Cavitary lesions are most commonly caused by squamous cell carcinoma (e.g., lung, head, and neck cancer)
- Cystic pulmonary metastasis: spread of malignant cells that form cystic lesions (contain a thin wall) in the lungs (e.g., colorectal cancer, soft tissue sarcomas, transitional cell carcinoma) [23][24]
“Four Carcinomas Route Hematogenously”: Follicular thyroid carcinoma, Choriocarcinoma, Renal cell carcinoma, and Hepatocellular carcinoma spread via the blood, compared to most carcinomas which spread lymphatically.
Mechanisms of metastasis
- Complex genetic changes are responsible for the selection of tumor subclones that are capable of metastasis.
- All metastases can be understood as arising from a two-part process: invasion of local extracellular tissue and dissemination and colonization.
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Invasion of extracellular tissue: loss of adhesion to the basement membrane → invasion through basement membrane → passage through extracellular tissue
- Loss of E-cadherin expression is associated with tumor metastatic potential.
- Overproduction of proteases such as collagenase and matrix metalloproteinases degrade the basement membrane and interstitial matrix. Neoplastic cells encounter various chemotactic and angiogenic factors in the newly exposed extracellular matrix.
- Autocrine signaling via tumor-produced cytokines and paracrine signaling by cleaved matrix components and extracellular growth factors stimulate tumor cell locomotion towards vasculature or lymphatics.
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Dissemination and colonization: encountering vascular or lymphatic routes → evasion of host defenses → implantation with distant tissue
- Host defenses destroy the majority of circulating cancer cells. Mechanisms to avoid this include tumor cell aggregation, formation of platelet-tumor complexes, and binding of active coagulation factors to form malignant emboli.
- Disruption of cellular adhesion molecules (laminins, cadherins) enables extravasation at distant tissues.
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Invasion of extracellular tissue: loss of adhesion to the basement membrane → invasion through basement membrane → passage through extracellular tissue
Common sites for cancer metastasis [25]
- The target organ for metastasis is usually the first capillary bed encountered by the neoplastic cells during spread.
- Certain types of cancer have a tendency to spread to particular organs (organ tropism; e.g., prostate cancer to bone, lung cancer to adrenal glands)
Common origins of cancer metastases | ||
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Organ with metastasis | Associated features | Primary tumor location |
Liver |
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Bone |
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Brain |
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Approximately 50% of brain tumors and most bone tumors are not primary tumors but rather result from metastases.
“Cancers spread progressively to the liver”: Colon, Stomach, and Pancreas cancers metastasize to the liver.
“BLT with a kosher pickle and mayo on the bun”: Breast, Lung, Thyroid, Kidney, Prostate cancers, and Multiple myeloma metastasize to the bone.
Tumor markers![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Definition: Substances produced by cancer cells that are found in increased amount in the bloodstream, urine, or body tissues.
- The most commonly tested tumor markers include the following
- Alpha fetoprotein (AFP)
- β-HCG
- Carcinoembryonic antigen (CEA)
- Prostate-specific antigen (PSA)
- Calcitonin
- Alkaline phosphatase
- Placental alkaline phosphatase
- Lactate dehydrogenase
- Neuron specific enolase (NSE)
- CA 19–9
- CA 15–3
- CA 125
- Chromogranin A
- S-100 protein
- β2 microglobulin
- Thyroglobulin
- Monoclonal immunoglobulins
For more details for each tumor marker see the article on tumor markers.
Conditions associated with tumors![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Neurocutaneous syndromes associated with neoplasms
Overview of neurocutaneous syndromes associated with neoplasms | |||||
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Condition | Key features | Neoplasms | |||
Neurofibromatosis type I |
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Neurofibromatosis type II |
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Tuberous sclerosis |
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von Hippel-Lindau syndrome |
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Sturge-Weber syndrome | |||||
Ataxia telangiectasia |
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Premalignant mucocutaneous conditions
Overview of premalignant mucocutaneous conditions | |||||
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Condition | Key features | Neoplasms | |||
Actinic keratosis |
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Bowen disease |
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Leukoplakia |
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Erythroplasia of Queyrat |
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Lentigo maligna | |||||
Dysplastic nevi | |||||
Xeroderma pigmentosum |
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Gastrointestinal conditions associated with neoplasms
Infectious conditions associated with neoplasms
Overview of infectious conditions associated with neoplasms | |||||
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Condition | Key features | Neoplasms | |||
DNA virus infections | EBV infection |
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HBV infection |
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HHV-8 infection |
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HPV 16 |
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HPV 18 | |||||
RNA virus infections | HTLV-1 infection |
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HIV infection |
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HCV infection |
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Nonviral pathogen infections | Schistosoma haematobium |
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Clonorchis sinensis (Chinese liver fluke) |
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Streptococcus bovis |
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Clostridium septicum |
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Miscellaneous conditions associated with neoplasms
Miscellaneous conditions associated with neoplasms | |||||
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Condition | Key features | Neoplasms | |||
Down syndrome |
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Paget disease of the bone |
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