- Clinical science
Oncology is the science of tumors. This learning card explains basic concepts relevant to the development, progression, spread, complications, diagnosis, and management 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. Therapy can be curative (mostly in early tumor stages) or palliative (mostly later stages). In addition to surgically removing a tumor, it can be beneficial to perform neoadjuvant (before surgery) and/or adjuvant (after surgery) radiation, chemotherapy, or both. Response rates to these forms of treatment are highly variable.
In addition to local effects, such as compression or infiltration of neighboring structures, malignant tumors can also cause systemic complications such as and cancer anorexia-cachexia syndrome. See the learning card on for more information.
|Normal cell|| |
|Carcinoma in situ (CIS)|
Benign and malignant tumors
|Benign tumor||Malignant tumor|
|Differentiation (grading)|| || |
|Microscopy|| || |
Metastasis and relapse
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|Cell origin||Benign tumor||Malignant tumor|
|Epithelial tumors|| || |
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|Special variants of mesenchymal tumors|| |
|Neuroectodermal tumors|| || |
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|Germ cell tumors|| || || |
|Embryonal tumors|| || |
In 2018, approximately 1.7 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 being more common than and .
Epidemiology of common cancer types in 2018
The following numbers are an estimation of new cancer cases and their mortality in the United States (excluding skin cancer).
|Type||Incidence/year in men||Incidence/year in women||Mortality/year|
|Lung and Bronchus||121,680||112,350||154,050|
- The most common cancer in men excluding skin cancer are:
- The most common cancer in women excluding skin cancer are:
- The cancer with the greatest mortality rate for both groups is cancer of lung and bronchus.
- 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.
- Mutations: duplication , insertion , deletion , point mutation
- Chromosomal translocation
- Amplification: increased gene expression
Key genes involved in carcinogenesis
Tumor suppressor genes
- Inhibits uncontrolled proliferation
- Apoptosis regulatory genes
Factors that affect key genes involved in carcinogenesis
- Exposure to risk factors
Properties of malignant cells
- Uncontrolled cell proliferation
- Failure to differentiate
- Failure of normal apoptotic pathways
- Defective DNA repair pathways
- Lack of response to external growth inhibiting signals
- Increased angiogenesis
- Shift in cellular metabolism (e.g., Warburg effect)
- Oncogene: Gain-of-function mutation converts a proto-oncogene into an oncogene which leads to overexpression of signaling proteins and growth factors → uncontrolled cellular proliferation (e.g., dysplasia, neoplasia).
Proto-oncogene: Genes that encode proteins that are important in normal cell division and 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
|Proto-oncogene||Chromosome||Gene product||Associated malignancies|
|BRAF|| ||Serine/threonine kinase|| |
|BCR-ABL|| ||Tyrosine kinase|| |
|JAK2|| || |
| ||Receptor tyrosine kinase|| |
|ALK|| || |
|RET|| || |
|c-KIT|| ||Cytokine receptor|| |
|L-myc-1 (MYCL1)|| ||Transcription factors|| |
|N-myc (MYCN)|| || |
|c-myc|| || |
|KRAS|| ||GTPase|| |
|BCL-2|| ||Antiapoptotic molecule|| |
|CDK4|| ||Cyclin-dependent kinase|
|CCND1|| ||Cyclin D protein (regulatory protein of the cell cycle)|| |
|ERBB1|| ||Epidermal growth factor receptor|| |
- Definition: A gene that normally controls and suppresses cell proliferation. Loss of function or inactivation leads to an increased risk of developing cancer. Both alleles need to be mutated in order for complete loss of function of the gene.
|Gene||Chromosome||Gene product||Associated malignancy|
|TP53|| || |
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|BRCA1|| || |
|BRCA2|| || |
|MMR gene family|| |
|SMAD4 (DPC4)|| |
|MEN 1|| |
|NF2|| || |
|TSC 2|| |
|VHL|| || |
|WT1|| || || |
|WT2|| || || |
|Benzene, Benzol|| |
|Vinyl chloride|| |
|Aromatic amines (β-Naphthylamine)|| |
|Wood dust|| || |
|Alkylating agents|| |
|Cigarette smoke|| |
|Arsenic|| || |
|Nonionizing radiation|| || |
|Ionizing radiation|| |
|Infective agent||Associated malignancies|
|Schistosoma haematobium|| |
|Clonorchis sinensis (Chinese liver fluke)|
|H. pylori|| |
- Definition: Process of classifying tumors based on their histological appearance (degree of differentiation).
Indicators of poor differentiation
- High-proliferation index
- Presence of nucleoli
- Giant cells with multiple nuclei
- Hyperchromasia and heterogenous 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
|Grading||Differentiation of malignant tissue|
|G1||Well differentiated (low grade)|
|G2||Moderate differentiation (intermediate grade)|
|G3||Poor differentiation (high grade)|
|G4||Undifferentiated / anaplastic (high grade)|
|GX||Differentiation cannot be assessed|
Cancer-specific grading systems
- Definition: Method of determining and classifying a tumor according to its spread throughout the body.
- Prognosis: Stage of the tumor is typically more important than the grade in determining the prognosis.
- TNM and AJCC systems are most commonly used
- T: size or direct extent of the primary tumor
- N: Involvement of regional lymph nodes
- M: Presence of distant metastasis
- By adding a "C" to any category, it's possible to express the certainty of the diagnosis
- C1: Routine procedure (clinical examination, x-ray)
- C2: Special procedure (e.g. ERCP, CT)
- C3: Based on biopsy, cytology or surgical exploration
- C4: Based on surgery and additional histopathological workup
- C5: Based on autopsy and histopathological workup
- By adding a prefix to TNM it's 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
Spread determines Stage, and Stage determines Survival more than grade!
Metastasis: spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)
- 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
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 → dissemination and colonization.
Invasion of extracellular tissue: loss of cellular adhesions → adhesion to 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 lympathic 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) enable extravasation at distant tissues. CD44 has been recently implicated in this process.
Common sites for cancer metastasis
- Brain metastases: appear in the white-gray matter junction as multiple well-circumscribed lesions
- Bone metastasis: usually involve the axial skeleton (e.g., vertebral column, pelvic girdle)
|Organ with metastasis||Primary tumor located in|
Generally, tumors in the brain (approximately 50%) and in the bone are most often metastatic rather than primary tumors!
- Definition: A syndrome characterized by progressive wasting of skeletal muscle mass with or without loss of body fat that occurs in patients with advanced cancer.
- Clinical features: weight loss, poor appetite, ↓ adipose tissue, muscle wasting, fatigue
- Diagnosis: no formal diagnostic criteria available, but some features for diagnosis include
- Prognosis: poor prognostic indicator
- Curative therapy: therapy with the intent of curing the disease
- Palliative therapy: therapy with the intent of relieving symptoms and improving quality of life
- Neoadjuvant therapy: : chemotherapy and/or radiation before elective surgery (e.g., preoperative radio-/chemotherapy in advanced rectal cancer)
- Adjuvant therapy: chemotherapy and/or radiation after surgery (e.g., postoperative chemotherapy in advanced colorectal cancer)
Modalities of antineoplastic therapy
- Surgery (e.g., hysterectomy, mastectomy, prostatectomy)
BEP regimen in seminoma )
- Combinations of multiple class of chemotherapy are often used to treat malignancy
- Cancers develop resistance by expressing multi-drug resistance protein 1 (also called P-glycoprotein)
- Hormone therapy (e.g. antiandrogens in prostate cancer)
- CD20 antibodies in non-Hodgkin lymphoma) (e.g.
Besides tumor grade and stage, it is important to consider the patient's performance status ( ), general well-being, comorbidities, and the patient's wishes when choosing a treatment option.