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.
|Basic terminology in oncology|
|Carcinoma in situ (CIS)|
Benign and malignant tumors
|Overview of benign and malignant tumors|
|Benign tumor||Malignant tumor|
|Differentiation (grading)|| || |
Metastasis and relapse
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|Types of tumors based on cell origin|
|Type of tumors||Cell origin||Benign tumor||Malignant tumor|
|Epithelial tumors|| |
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|Special variants of mesenchymal tumors|| || |
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|Neuroectodermal tumors|| || |
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|Germ cell tumors|| || || |
|Embryonal tumors|| || |
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. 
Epidemiology of common cancer types in 2020 
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|
|Incidence/year in men||Incidence/year in women||Mortality/year|
|Lung and bronchus cancer||116,300||112,520||135,720|
- The most common types of cancer in men (excluding skin cancer)
- The most common cancer in women (excluding skin cancer)
- The types of cancer with the highest mortality rate in both men and women (in descending order)
- The most common types of cancer that have the greatest mortality rate in children (< 15 years)
- 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
Properties of malignant cells
- Sustained proliferative signaling: due to mutation of genes regulating cell division and growth
- Evade growth suppressors 
- Genome instability and mutations
- Resist cell death
- Enable replicative immortality: telomerase reactivation → ↑ length of telomeres → ↑ number of possible cell replication cycles
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. 
Induce angiogenesis 
- 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:
- 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 
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
Immune checkpoints 
- Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
Programmed death-ligand system
- Expression of 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.
- is inhibited by cancer immunotherapy agents nivolumab and pembrolizumab.
Development of resistance to chemotherapeutic agents
- Expression of multidrug resistance protein 1 (MDR1; also called P-glycoprotein). 
- 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: the product of a in a proto-oncogene which leads to overexpression of signaling proteins and growth factors, and thus, uncontrolled cellular proliferation (e.g., dysplasia, neoplasia)
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)
- Ligand-directed transcription factors (intracellular hormone receptors)
- GTP-binding proteins
- Tyrosine kinase receptors
- Growth factors and cytokines
|Overview of proto-oncogenes |
|Proto-oncogene||Chromosome||Gene product||Associated malignancies|
|BRAF|| || |
|BCR-ABL|| || |
|JAK2|| || |
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|RET|| || |
|c-KIT|| || |
|L-myc-1 (MYCL1)|| || |
|N-myc (MYCN)|| || |
|c-myc|| || |
|KRAS|| || |
|BCL-2|| || |
|CDK4|| || |
|CCND1|| || |
L-myc is associated with lung cancer and n-myc with neuroblastoma.
BCL-2 mutations are associated with diffuse large B-cell lymphoma.
Tumor suppressor genes
- Tumor suppressor gene: a gene that normally controls and suppresses cell proliferation
|Overview of tumor suppressor genes|
|Gene||Chromosome||Gene product||Associated malignancy|
|TP53|| || |
|APC gene|| |
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|BRCA1|| || |
|MMR gene family|| |
|DCC (Deleted in colorectal cancer)|| |
|SMAD4 (DPC4) (Deleted in pancreatic cancer)|| |
|MEN 1|| |
|NF2|| || |
|TSC1 (Tuberous sclerosis complex 1)|| |
|TSC2 (Tuberous sclerosis complex 2)|| |
|VHL|| || |
|WT1 (Wilms Tumor 1)|| || || |
|WT2 (Wilms Tumor 2)|| |
PTEN mutation is associated with cancers of the Prostate, breasT, and ENdometrium.
|Examples of chemical carcinogens|
|Substance||Sources of exposure||Malignancy|
|Aromatic amines (β-naphthylamine, benzidine)|
|Benzene, benzol|| |
|Cigarette smoke|| |
|Wood dust|| |
|Overview of radiation|
|Nonionizing radiation|| || |
|Ionizing radiation|| |
|Infective agent||Associated malignancies|
|Schistosoma haematobium|| |
|Clonorchis sinensis (Chinese liver fluke)|
- Definition: the process of classifying tumors based on their histological appearance (degree of cell differentiation)
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
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|
|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.|
- Cancer-specific grading systems
Tumor staging 
- 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.
- T stage: size or direct extent of the primary tumor
- N stage: involvement of regional lymph nodes
- M stage: presence of distant metastasis
- 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: the spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)
Types of metastasis 
- Lymphatic metastasis
- Hematogenous metastasis
- 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)
- Cavitating pulmonary metastasis 
- 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) 
“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.
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.
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.
- Invasion of extracellular tissue: loss of adhesion to the basement membrane → invasion through basement membrane → passage through extracellular tissue
Common sites for cancer metastasis 
- 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|
|Organ with metastasis|| |
|Primary tumor location|
“BLT with a kosher pickle and mayo on the bun”: Breast, Lung, Thyroid, Kidney, Prostate cancers, and Multiple myeloma metastasize to the bone.
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
For more details for each tumor marker see the article on .
|Overview of neurocutaneous syndromes associated with neoplasms|
|Neurofibromatosis type I|| |
|Neurofibromatosis type II|| |
|von Hippel-Lindau syndrome|| |
Premalignant mucocutaneous conditions
|Overview of premalignant mucocutaneous conditions|
|Actinic keratosis|| |
|Bowen disease|| |
|Erythroplasia of Queyrat|| || |
|Overview of gastrointestinal conditions associated with neoplasms|
|Inflammatory bowel disease||Ulcerative colitis|| |
|Atrophic gastritis||Autoimmune metaplastic atrophic gastritis (AMAG)|
|Environmental metaplastic atrophic gastritis (EMAG)|| |
Infectious conditions associated with neoplasms
|Overview of infectious conditions associated with neoplasms|
|DNA virus infections||EBV infection|
|HHV-8 infection|| |
|RNA virus infections||HTLV-1 infection|
|Nonviral pathogen infections||Schistosoma haematobium|| |
|Clonorchis sinensis (Chinese liver fluke)|
|Streptococcus bovis|| |
|Clostridium septicum|| |
Miscellaneous conditions associated with neoplasms
|Miscellaneous conditions associated with neoplasms|
|Paget disease of the bone|