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National Cancer Institute definition neoplasia benign malignant carcinoma in situ metastasis

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Introduction: Neoplasia and Tumour Metastasis

Neoplasia refers to abnormal and uncontrolled new growth of cells that persists even after the original stimulus has ceased. This growth forms a neoplasm, commonly called a tumour. Neoplasms may be benign or malignant. Benign tumours are generally slow-growing, well-localised masses that do not invade surrounding tissues or spread to distant sites. In contrast, malignant tumours, or cancers, can invade adjacent structures, destroy normal tissues, and spread to other parts of the body.

Tumours are named according to their tissue of origin. A malignant tumour arising from epithelial cells is called a carcinoma, whereas one arising from mesenchymal tissues is called a sarcoma. Cancer cells often show reduced differentiation and loss of normal structural and functional characteristics, a feature known as anaplasia.

Carcinoma in situ represents a pre-invasive stage of epithelial malignancy. The cells show malignant microscopic features but remain confined above the basement membrane, without invasion into the underlying tissue. Once tumour cells breach the basement membrane, the tumour becomes invasive and gains the potential to metastasise.

Metastasis is the spread of malignant cells from the primary tumour to distant, non-contiguous sites, where they establish secondary tumours. It is a defining feature of malignancy and occurs mainly through lymphatic channels, blood vessels, or seeding of body cavities. Understanding tumour behaviour and pathways of spread is essential for cancer diagnosis, staging, treatment planning, and prognosis.

This topic covers the nomenclature of neoplasms, differences between normal and cancer cells, benign and malignant tumours, carcinoma in situ, and the mechanisms and routes of tumour metastasis. This aligns with the organisation of Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 237-243.

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Neoplasia means “new growth.” It is an abnormal, clonal proliferation of cells that grows excessively and relatively autonomously, even when the stimulus that initiated it is no longer present. A neoplasm may be benign or malignant. Malignant neoplasms are cancers: they can invade surrounding tissues and may spread to distant organs by metastasis. Cancer develops through accumulated genetic and epigenetic changes that disrupt normal controls of cell growth, death, differentiation, and DNA repair. The National Cancer Institute overview describes cancer as uncontrolled cell growth with the potential to spread.

A detailed study of neoplasia includes:

Basic definitions and terminology
- Neoplasia, neoplasm, tumour, cancer
- Differences from hyperplasia, hypertrophy, metaplasia, and dysplasia
- Nomenclature of benign and malignant tumours
Benign versus malignant tumours
- Differentiation and anaplasia
- Rate of growth
- Local invasion
- Metastasis
- Effects on the patient
Cancer cell biology
- Hallmarks of cancer
- Sustained proliferation and avoidance of growth inhibition
- Evasion of apoptosis and immune destruction
- Angiogenesis, invasion, and metastatic capability
Molecular basis of cancer
- Oncogenes and proto-oncogenes
- Tumour-suppressor genes such as TP53 and RB
- DNA-repair genes
- Multistep carcinogenesis and clonal evolution
Precancerous changes
- Dysplasia
- Carcinoma in situ
- Progression to invasive carcinoma
Tumour progression and metastasis
- Local invasion
- Lymphatic, haematogenous, and transcoelomic spread
- Tumour-host interactions and angiogenesis
Clinical effects, grading, staging, and diagnosis
- Local and systemic effects
- Cancer cachexia and paraneoplastic syndromes
- Tumour grade and TNM stage
- Principles of pathological diagnosis

Robbins, Cotran & Kumar Pathologic Basis of Disease identifies differentiation/anaplasia, local invasion, and metastasis as the main features distinguishing most benign and malignant neoplasms, p. 239-243.

Which section should I explain in full first: (1) basics and nomenclature, (2) benign vs malignant tumours, (3) molecular basis, (4) carcinoma in situ, or (5) metastasis?

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Neoplasia

Neoplasia literally means “new growth.” It is an abnormal, excessive, and uncoordinated proliferation of cells that continues even after the initiating stimulus has stopped. The resulting mass is called a neoplasm or tumour.

A tumour is not always cancer. It can be:

Benign - non-cancerous and usually localised.
Malignant - cancerous, capable of invading surrounding tissues and spreading to distant organs.

The NCI definition of tumour notes that tumours may form when cells divide more than they should or fail to die when they should.

1. Normal cell growth versus neoplastic growth

Normal tissues maintain a balance between:

Cell proliferation
Differentiation into specialised cells
Cellular ageing
Programmed cell death, called apoptosis

This balance is regulated by growth factors, hormones, cell-cycle checkpoints, tumour-suppressor genes, and DNA-repair mechanisms.

In neoplasia, mutations accumulate in a cell. These mutations allow the cell and its descendants to grow independently of normal regulatory signals. Because the tumour begins from one altered cell that multiplies, most neoplasms are clonal in origin.

2. Difference between neoplasia and other adaptive changes

Condition	Meaning	Reversibility
Hyperplasia	Increase in the number of normal cells in response to a stimulus	Usually reversible
Hypertrophy	Increase in cell size	Usually reversible
Metaplasia	Replacement of one mature cell type by another mature cell type	Usually reversible
Dysplasia	Disordered growth and maturation of cells, often in epithelium	May be reversible, but can progress
Neoplasia	Autonomous, clonal new growth caused by genetic alterations	Generally irreversible

Example: Chronic smoking can cause squamous metaplasia in bronchial epithelium. Continued injury may lead to dysplasia, then carcinoma in situ, and eventually invasive carcinoma.

3. Classification of neoplasms

Neoplasms are broadly classified as benign or malignant.

A. Benign neoplasms

Benign tumours remain localised and do not metastasise. They are usually slow-growing and well-differentiated, meaning that their cells closely resemble the normal tissue from which they arose.

Examples:

Lipoma - benign tumour of fat tissue
Fibroma - benign tumour of fibrous tissue
Adenoma - benign tumour of glandular epithelium
Papilloma - benign epithelial tumour producing finger-like projections
Leiomyoma - benign tumour of smooth muscle, for example uterine fibroid

Although benign tumours do not metastasise, they can still be dangerous. For example, a benign tumour in the brain may compress essential structures, and an endocrine adenoma may produce excessive hormones.

B. Malignant neoplasms

Malignant tumours are called cancers. They may destroy local tissue, invade nearby organs, recur after treatment, and metastasise to distant sites.

Malignant tumours are classified by their tissue of origin:

Carcinoma - malignant tumour arising from epithelial cells
Examples: squamous cell carcinoma, adenocarcinoma.
Sarcoma - malignant tumour arising from connective or mesenchymal tissues
Examples: osteosarcoma, fibrosarcoma, liposarcoma.
Leukaemia - malignant tumour of blood-forming cells, usually in bone marrow.
Lymphoma - malignant tumour of lymphoid tissue.
Melanoma - malignant tumour of melanocytes.

4. Benign versus malignant neoplasms

The three key pathological criteria used to distinguish benign from malignant tumours are:

Differentiation and anaplasia
Local invasion
Metastasis

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 239-243.

Feature	Benign tumour	Malignant tumour
Differentiation	Well differentiated, resembles tissue of origin	Often poorly differentiated or anaplastic
Growth rate	Usually slow	Variable, often faster
Margins	Well circumscribed, sometimes encapsulated	Irregular, poorly circumscribed
Local invasion	Does not invade adjacent tissue	Invades and destroys adjacent tissues
Metastasis	Absent	May be present
Recurrence after removal	Uncommon if fully removed	More likely

The NCI cancer overview explains that benign tumours do not invade nearby tissue, whereas cancerous tumours can invade and spread.

5. Differentiation and anaplasia

Differentiation refers to how closely tumour cells resemble their normal cells of origin in appearance and function.

A well-differentiated tumour closely resembles the parent tissue.
A poorly differentiated tumour shows less resemblance.
Anaplasia means lack of differentiation and is a characteristic feature of many malignant tumours.

Microscopic features of anaplasia

Pleomorphism - variation in size and shape of cells and nuclei
Hyperchromatic nuclei - darkly stained nuclei due to excess DNA
High nucleus-to-cytoplasm ratio
Large, irregular nucleoli
Numerous or abnormal mitoses
Loss of normal tissue architecture
Tumour giant cells

Anaplasia usually indicates aggressive biological behaviour, but the diagnosis of malignancy also depends on evidence of invasion or metastasis.

6. Dysplasia and carcinoma in situ

Dysplasia means disordered cellular growth. It is usually seen in epithelial tissues such as the cervix, skin, oral cavity, and bronchial epithelium.

Microscopic features include:

Loss of uniformity of cells
Cellular pleomorphism
Enlarged, hyperchromatic nuclei
Increased mitotic activity
Disturbed arrangement and maturation of cells

Dysplasia is not always cancer. Mild or moderate dysplasia may regress if the damaging stimulus is removed. However, severe dysplasia is more likely to progress.

Carcinoma in situ occurs when dysplastic changes involve the full thickness of the epithelium but tumour cells have not penetrated the basement membrane. It is therefore a pre-invasive malignancy.

Examples include:

Cervical carcinoma in situ
Ductal carcinoma in situ of the breast
Squamous cell carcinoma in situ of skin

Once cells cross the basement membrane, the tumour is called invasive carcinoma and has access to lymphatic and blood vessels, creating the possibility of metastasis. Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 241.

7. Molecular basis of neoplasia

Cancer is fundamentally a genetic disease. It occurs when genetic and epigenetic alterations affect genes that control cell multiplication, survival, and genome stability.

The main affected gene groups are:

A. Proto-oncogenes and oncogenes

Proto-oncogenes normally promote controlled growth. When mutated, amplified, or overexpressed, they become oncogenes, which drive continuous proliferation.

Examples:

RAS
MYC
ERBB2/HER2
BCR-ABL

B. Tumour-suppressor genes

These genes normally restrain cell growth, repair DNA damage, or induce apoptosis. Loss of their function permits survival and proliferation of abnormal cells.

Examples:

TP53 - responds to DNA damage by arresting the cell cycle or causing apoptosis
RB - regulates progression from G1 to S phase of the cell cycle
APC - important in colorectal tumour development
BRCA1 and BRCA2 - involved in DNA repair

C. DNA-repair genes

Defects in DNA-repair systems lead to genomic instability and allow mutations to accumulate.

Examples:

BRCA1/BRCA2
Mismatch-repair genes such as MLH1 and MSH2

The NCI genetics resource describes proto-oncogenes, tumour-suppressor genes, and DNA-repair genes as the main gene classes involved in cancer development.

8. Hallmarks of cancer

Cancer cells acquire several functional abilities that allow them to survive and progress:

Sustained proliferative signalling
Resistance to growth-inhibitory signals
Evasion of apoptosis
Limitless replicative capacity
Induction of angiogenesis
Invasion and metastasis
Reprogramming of energy metabolism
Evasion of immune destruction
Genomic instability
Tumour-promoting inflammation

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 250-252.

9. Tumour growth and angiogenesis

A tumour needs oxygen and nutrients to grow. When it becomes larger than approximately 1 to 2 mm, diffusion alone is inadequate. Tumour cells then stimulate the formation of new blood vessels, called angiogenesis.

A key angiogenic factor is vascular endothelial growth factor (VEGF). New tumour vessels are often abnormal, leaky, and poorly organised, but they support tumour expansion and provide routes for cancer cells to enter the circulation.

10. Tumour invasion and metastasis

Invasion is direct extension of tumour cells into adjacent tissues. It is a defining feature of malignant tumours.

Metastasis is the development of secondary tumour deposits at sites distant from the primary tumour. It is one of the strongest indicators of malignancy.

The major routes of spread are:

Lymphatic spread - common in carcinomas
Example: breast carcinoma spreading to axillary lymph nodes.
Haematogenous spread - common in sarcomas, though carcinomas can also spread this way
Common sites: liver, lungs, bone, and brain.
Transcoelomic seeding - spread across body cavities
Example: ovarian carcinoma spreading throughout the peritoneal cavity.

11. Causes and risk factors for neoplasia

Cancer usually results from interaction between genetic susceptibility and environmental exposure.

Important risk factors include:

Tobacco use
Alcohol
Ultraviolet and ionising radiation
Obesity and dietary factors
Chronic inflammation
Occupational carcinogens, such as asbestos and benzene
Oncogenic infections:
- Human papillomavirus - cervical and anogenital cancers
- Hepatitis B and C viruses - hepatocellular carcinoma
- Epstein-Barr virus - some lymphomas and nasopharyngeal carcinoma
- Helicobacter pylori - gastric adenocarcinoma and lymphoma
Inherited mutations, for example BRCA mutations or familial adenomatous polyposis

Key points

Neoplasia is autonomous, clonal, abnormal cellular proliferation.
A neoplasm may be benign or malignant.
Malignancy is identified mainly by anaplasia, local invasion, and metastasis.
Carcinoma in situ is a full-thickness epithelial abnormality without basement membrane invasion.
Cancer results from accumulated genetic alterations affecting oncogenes, tumour-suppressor genes, and DNA-repair genes.
Metastasis is the major cause of morbidity and death in many cancers.

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Nomenclature of Neoplasms

Nomenclature means the system used to name tumours. Tumour names are generally based on:

The cell or tissue of origin
Whether the tumour is benign or malignant
Sometimes, its microscopic pattern or gross appearance

The suffix “-oma” means tumour or swelling. However, there are important exceptions, so a name ending in “-oma” does not always mean benign.

1. Naming benign tumours

A. Benign tumours of mesenchymal origin

Mesenchymal tissues include connective tissue, fat, cartilage, bone, muscle, and blood vessels.

The usual rule is:

Name of tissue/cell + “oma” = benign tumour

Tissue of origin	Benign tumour	Meaning
Fibrous tissue	Fibroma	Benign tumour of fibroblasts
Fat	Lipoma	Benign tumour of adipose tissue
Cartilage	Chondroma	Benign tumour of cartilage
Bone	Osteoma	Benign tumour of bone
Smooth muscle	Leiomyoma	Benign smooth-muscle tumour
Skeletal muscle	Rhabdomyoma	Benign skeletal-muscle tumour
Blood vessels	Hemangioma	Benign vascular tumour
Lymphatic vessels	Lymphangioma	Benign lymphatic-vessel tumour

Examples:

A lipoma is a benign mass made of mature fat cells.
A uterine leiomyoma, also called a fibroid, is a benign tumour of smooth muscle in the uterus.

B. Benign epithelial tumours

Naming epithelial tumours is more complex because the name may depend on their cell of origin, microscopic structure, or gross appearance.

1. Adenoma

An adenoma is a benign epithelial neoplasm that forms glands or arises from glandular epithelium.

Examples:

Thyroid adenoma
Adrenal adenoma
Colonic adenoma
Pituitary adenoma

An adenoma need not form an obvious gland. For example, a benign epithelial tumour arising from renal tubular epithelium may still be called an adenoma.

2. Papilloma

A papilloma is a benign epithelial tumour that produces finger-like or wart-like projections from an epithelial surface.

Examples:

Squamous papilloma of skin or oral cavity
Urothelial papilloma of the urinary bladder

3. Cystadenoma

A cystadenoma is a benign glandular epithelial tumour that forms cystic spaces.

Examples:

Ovarian serous cystadenoma
Ovarian mucinous cystadenoma

4. Polyp

A polyp is a mass that projects above a mucosal surface, such as in the colon, stomach, nasal cavity, or uterus.

“Polyp” describes the shape or gross appearance, not necessarily the histological nature. A polyp may be:

Non-neoplastic, for example an inflammatory nasal polyp
Benign neoplastic, for example an adenomatous colonic polyp
Malignant, in some cases

2. Naming malignant tumours

Malignant tumours are mainly divided into carcinomas and sarcomas.

A. Carcinoma

A carcinoma is a malignant tumour arising from epithelial cells. Epithelia cover body surfaces, line organs and cavities, and form glands.

Type	Description	Example
Squamous cell carcinoma	Malignant tumour of squamous epithelium	Cancer of skin, cervix, oral cavity, oesophagus
Adenocarcinoma	Malignant gland-forming epithelial tumour	Cancer of colon, prostate, breast, stomach
Urothelial carcinoma	Malignant tumour of transitional urothelium	Urinary bladder carcinoma
Basal cell carcinoma	Malignant tumour of basal epidermal cells	Basal cell carcinoma of skin

Example:
A malignant gland-forming epithelial tumour in the colon is called colonic adenocarcinoma.

B. Sarcoma

A sarcoma is a malignant tumour arising from mesenchymal or connective tissues.

The general rule is:

Name of tissue/cell + “sarcoma” = malignant tumour

Tissue of origin	Malignant tumour
Fibrous tissue	Fibrosarcoma
Fat	Liposarcoma
Cartilage	Chondrosarcoma
Bone	Osteosarcoma
Smooth muscle	Leiomyosarcoma
Skeletal muscle	Rhabdomyosarcoma
Blood vessels	Angiosarcoma

Example:
An osteosarcoma is a malignant tumour that produces bone or osteoid.

3. Tumours with special names

Some tumours have historical names that do not follow the usual nomenclature rules.

A. Malignant tumours ending in “-oma”

These are important exceptions because they are malignant despite ending in “-oma.”

Tumour	Nature
Melanoma	Malignant tumour of melanocytes
Lymphoma	Malignant tumour of lymphoid cells
Leukaemia	Malignant neoplasm of haematopoietic cells, usually involving marrow and blood
Mesothelioma	Usually malignant tumour of mesothelial cells
Hepatoma	Traditional term for hepatocellular carcinoma, a malignant liver tumour
Seminoma	Malignant germ-cell tumour of testis
Glioma	A tumour of glial cells, may be benign or malignant depending on type and grade

Therefore, the suffix “-oma” should never alone be used to decide whether a tumour is benign.

B. Tumours named according to their cell type

Tumour	Cell/tissue of origin
Melanoma	Melanocytes
Lymphoma	Lymphocytes and lymphoid cells
Leukaemia	Bone marrow blood-forming cells
Mesothelioma	Mesothelial lining of pleura, peritoneum, or pericardium
Germ-cell tumour	Germ cells of gonads or extragonadal sites
Neuroblastoma	Primitive sympathetic nervous-system cells
Retinoblastoma	Primitive retinal cells
Wilms tumour (nephroblastoma)	Primitive kidney tissue in children

4. Mixed tumours

A mixed tumour contains more than one type of neoplastic cell or shows more than one pattern of differentiation.

Pleomorphic adenoma

The classic example is pleomorphic adenoma of the salivary gland, often called a benign mixed tumour.

It contains epithelial and myoepithelial tumour cells.
The tumour cells may produce a myxoid, cartilaginous, or fibrous-looking stroma.
Despite its mixed appearance, it usually arises from a single clone of cells.

Carcinosarcoma

A carcinosarcoma is a malignant tumour containing both:

Carcinomatous component: malignant epithelial tissue
Sarcomatous component: malignant mesenchymal-looking tissue

It may occur in the uterus and other organs.

5. Hamartoma and choristoma

These are not true neoplasms, but they are often confused with tumours.

Hamartoma

A hamartoma is a disorganised mass of mature tissue normally found at that site.

Example: Pulmonary hamartoma, which may contain cartilage, fat, and connective tissue in the lung.

Choristoma

A choristoma is normal mature tissue present in an abnormal location.

Example: Pancreatic tissue found in the wall of the stomach or small intestine.

6. Important terminology

Term	Meaning
Neoplasm	Autonomous abnormal new growth of cells
Tumour	A mass caused by abnormal cell proliferation; often used synonymously with neoplasm
Benign	Localised tumour that does not invade or metastasise
Malignant	Tumour capable of invasion and metastasis
Carcinoma	Malignant epithelial tumour
Sarcoma	Malignant mesenchymal tumour
Adenoma	Benign epithelial tumour of glandular origin or forming glands
Papilloma	Benign epithelial tumour with finger-like projections
Polyp	Mucosal projection, which may or may not be neoplastic
Carcinoma in situ	Full-thickness epithelial malignancy without invasion through the basement membrane

Easy summary

Benign mesenchymal tumour: tissue name + oma
Example: fat → lipoma
Malignant mesenchymal tumour: tissue name + sarcoma
Example: fat → liposarcoma
Malignant epithelial tumour: carcinoma
Example: glandular epithelium → adenocarcinoma
Do not assume that all tumours ending in “-oma” are benign.
Examples of malignant “-oma” tumours include melanoma, lymphoma, mesothelioma, and seminoma.

Robbins & Kumar Basic Pathology explains that benign mesenchymal tumours are generally named by adding “-oma” to their cell of origin, while malignant epithelial tumours are carcinomas and malignant mesenchymal tumours are sarcomas, p. 187-188.

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Normal Cells and Cancer Cells

Cells are the basic structural and functional units of the body. In healthy tissues, normal cells grow, divide, perform specialised functions, and die in a tightly controlled manner. Cancer cells arise when accumulated genetic and epigenetic changes disrupt these controls. They continue to grow and survive when they should stop, and some acquire the ability to invade and spread.

The NCI explanation of cancer states that cancer begins when abnormal cells grow and multiply when they should not.

1. Normal cells

Normal cells have the following properties:

A. Controlled cell division

Normal cells divide only when needed, such as:

During growth and development
To replace worn-out cells
During wound healing
In response to appropriate growth factors or hormones

Their progress through the cell cycle is regulated at checkpoints. If DNA is damaged, the cell may pause division to repair the damage. If it cannot be repaired, the cell undergoes apoptosis.

B. Differentiation

Normal cells become specialised to perform particular functions.

Examples:

Red blood cells transport oxygen.
Neurons conduct electrical impulses.
Hepatocytes carry out metabolic and detoxification functions.
Muscle cells contract.
Glandular epithelial cells produce secretions.

They usually retain the appearance, organisation, and function appropriate to their tissue.

C. Response to growth-regulating signals

Normal cells respond to signals that tell them to:

Divide
Stop dividing
Differentiate
Repair DNA
Undergo programmed cell death

Important protective genes include tumour-suppressor genes, such as TP53 and RB, which prevent uncontrolled proliferation.

D. Contact inhibition and anchorage dependence

Normal cells usually stop growing when they come into contact with neighbouring cells. This is called contact inhibition.

Many normal cells also need attachment to the extracellular matrix to survive and divide. This is called anchorage dependence. Loss of attachment often triggers apoptosis, preventing misplaced cells from surviving.

E. Limited life span

Most normal somatic cells have a limited capacity for division. With repeated replication, telomeres shorten and the cell eventually enters senescence or dies.

F. Orderly cell death

Damaged, aged, or unnecessary cells are removed by apoptosis. This protects the body from accumulation of cells with dangerous DNA mutations.

2. How normal cells become cancer cells

Cancer develops through a multistep process. A normal cell gradually acquires mutations in genes that regulate growth, survival, and DNA repair.

The important gene groups are:

Gene group	Normal role	Change in cancer
Proto-oncogenes	Promote normal controlled cell growth	Become oncogenes that drive excessive growth
Tumour-suppressor genes	Inhibit cell division, repair damage, or induce apoptosis	Are lost or inactivated
DNA-repair genes	Correct DNA errors	Become defective, causing mutations to accumulate
Apoptosis-regulating genes	Remove damaged cells	Allow abnormal cells to survive

For example:

RAS mutations can continuously stimulate cell proliferation.
Loss of TP53 prevents proper DNA-damage response and apoptosis.
Loss of RB removes an important cell-cycle brake.
BRCA1/BRCA2 defects impair DNA repair.

A single mutation is usually not enough to produce cancer. Malignancy commonly develops after multiple alterations accumulate over time.

3. Characteristics of cancer cells

Cancer cells differ from normal cells in several important ways.

A. Uncontrolled proliferation

Cancer cells can divide without normal external growth signals. They may produce their own growth factors or activate growth-signalling pathways continuously.

Normal cells: divide only when required.
Cancer cells: divide continuously or excessively.

B. Resistance to growth inhibition

Normal cells respond to signals that stop cell division. Cancer cells often ignore these signals because tumour-suppressor pathways are damaged.

For example, inactivation of the RB pathway allows cells to pass through the cell cycle even when they should stop.

C. Evasion of apoptosis

Cells with severe DNA damage should undergo apoptosis. Cancer cells may avoid apoptosis by:

Losing TP53 function
Increasing anti-apoptotic proteins such as BCL-2
Decreasing pro-apoptotic signals

This allows genetically abnormal cells to survive and multiply.

D. Replicative immortality

Normal cells eventually stop dividing because telomeres shorten. Many cancer cells activate telomerase, an enzyme that maintains telomeres and permits repeated cell division.

E. Reduced differentiation and anaplasia

Cancer cells may lose the appearance and function of the normal tissue from which they arise.

This lack of differentiation is called anaplasia. Microscopically, anaplastic cells may show:

Pleomorphism: variation in cell and nuclear size and shape
Enlarged, dark-staining nuclei: hyperchromasia
High nuclear-to-cytoplasmic ratio
Prominent nucleoli
Numerous or abnormal mitotic figures
Loss of normal tissue architecture

Some cancers remain well differentiated, while high-grade cancers are often poorly differentiated or undifferentiated.

F. Altered metabolism

Cancer cells need large amounts of energy and cellular building blocks for rapid growth. Many cancer cells use increased glucose uptake and glycolysis even when oxygen is present. This is called the Warburg effect.

This high glucose uptake is one reason why FDG-PET imaging can help detect many cancers.

G. Angiogenesis

A tumour cannot grow beyond a small size without an adequate blood supply. Cancer cells can stimulate formation of new blood vessels by releasing angiogenic factors, particularly vascular endothelial growth factor (VEGF).

These vessels provide oxygen and nutrients and also give tumour cells access to the bloodstream.

H. Invasion and metastasis

Unlike normal cells, malignant cancer cells may:

Detach from neighbouring cells
Break down surrounding extracellular matrix and basement membrane
Invade nearby tissues
Enter lymphatic vessels or blood vessels
Travel to distant organs
Form secondary tumours, called metastases

Metastasis is a defining feature of malignant tumours.

I. Immune evasion

The immune system can recognise and destroy some abnormal cells. Cancer cells may escape immune destruction by:

Reducing tumour-antigen visibility
Creating an immunosuppressive microenvironment
Expressing proteins such as PD-L1 that inhibit T-cell activity

This property is the basis for some immunotherapies.

4. Normal cells versus cancer cells

Feature	Normal cells	Cancer cells
Growth	Controlled and regulated	Excessive and relatively autonomous
Response to growth signals	Divide only when stimulated appropriately	May grow without external stimulation
Response to stop signals	Stop dividing when required	Often ignore growth-inhibitory signals
Apoptosis	Die when damaged or no longer needed	Resist apoptosis
Differentiation	Well differentiated and specialised	May be poorly differentiated or anaplastic
Shape and nucleus	Uniform size and shape	Pleomorphism, hyperchromasia, abnormal nuclei
Contact inhibition	Present	Often lost
Anchorage dependence	Usually required	May be lost
Replicative capacity	Limited	Often unlimited due to telomerase activation
Metabolism	Balanced energy production	Increased glucose uptake and altered metabolism
Angiogenesis	Occurs only when physiologically needed	Stimulates new vessel formation
Invasion	Remain within normal boundaries	May invade neighbouring tissues
Metastasis	Never metastasise	May spread through lymph, blood, or body cavities
Genetic stability	Usually maintained by repair mechanisms	Often genetically unstable

5. Progression from normal cell to cancer

A simplified sequence is:

Normal epithelium → hyperplasia → dysplasia → carcinoma in situ → invasive carcinoma → metastasis

Hyperplasia: increased number of cells, but cells look normal.
Dysplasia: disordered growth with abnormal cell appearance and arrangement.
Carcinoma in situ: severe dysplasia involving the full epithelial thickness, but the basement membrane is intact.
Invasive carcinoma: tumour cells penetrate the basement membrane and invade surrounding tissue.
Metastatic carcinoma: cells establish secondary deposits at distant sites.

Not all hyperplasia or dysplasia progresses to cancer. Progression depends on the type of lesion, persistence of the cause, and accumulation of further genetic changes.

6. Hallmarks of cancer cells

Cancer cells acquire a group of functional capabilities called the hallmarks of cancer:

Sustained proliferative signalling
Evasion of growth suppressors
Resistance to cell death
Replicative immortality
Induction of angiogenesis
Invasion and metastasis
Reprogrammed cellular metabolism
Avoidance of immune destruction
Genome instability and mutation
Tumour-promoting inflammation

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 250-252.

Key takeaway

A normal cell obeys the body’s rules of growth, differentiation, repair, and death. A cancer cell has genetic abnormalities that allow it to ignore these rules, survive abnormally, multiply excessively, invade tissue, and sometimes metastasise.

Diagram of normal and abnormal cells

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educational diagram comparing normal cells with cancer cells showing uncontrolled cell growth

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NCI diagram normal cells versus cancer cells uncontrolled growth

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Educational medical diagram comparing normal cells and cancer cells side by side. Left panel: neatly arranged, uniform epithelial cells with small regular nuclei, intact basement membrane, labels: controlled division, normal differentiation, apoptosis of damaged cells. Right panel: crowded disorganized pleomorphic cancer cells with enlarged dark irregular nuclei, many mitoses, basement membrane breached with cells invading connective tissue, labels: uncontrolled growth, loss of differentiation, invasion. Include a clear title: Normal Cells vs Cancer Cells.

Diagram: Normal Cells vs Cancer Cells

Educational diagram comparing normal cells with cancer cells

Key interpretation:

Normal cells: uniform in size and shape, arranged in an orderly pattern, have regular nuclei, divide only when needed, and remain above the basement membrane.
Cancer cells: variable in size and shape, crowded and disorganised, possess enlarged dark irregular nuclei, divide excessively, and can breach the basement membrane to invade surrounding tissue.

Explain benign and malignant tumours

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educational pathology diagram comparison benign tumor malignant tumor invasion metastasis

Benign and Malignant Tumours

A tumour, or neoplasm, is an abnormal mass of cells produced by excessive and relatively autonomous cell proliferation. Tumours are classified as benign or malignant according to their biological behaviour.

Benign tumours are non-cancerous. They remain localised and do not invade or metastasise.
Malignant tumours are cancers. They invade surrounding tissues and can spread to distant sites, forming secondary tumours called metastases.

The most reliable distinctions are differentiation/anaplasia, local invasion, and metastasis. Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 239-243.

1. Benign tumours

A benign tumour is a localised neoplasm that usually grows slowly and remains confined to its site of origin.

Features

Cells are usually well differentiated and resemble the normal cells from which they developed.
Growth is generally slow, though exceptions occur.
The tumour is often well-circumscribed and may be enclosed by a fibrous capsule.
It expands by pushing on adjacent tissue rather than infiltrating it.
It does not invade surrounding tissue.
It never metastasises.
Complete surgical removal is usually curative.

Examples

Tissue	Benign tumour
Fat	Lipoma
Fibrous tissue	Fibroma
Cartilage	Chondroma
Smooth muscle	Leiomyoma
Glandular epithelium	Adenoma
Blood vessels	Hemangioma

Can benign tumours be dangerous?

Yes. “Benign” does not always mean harmless. A benign tumour can produce serious disease because of:

Compression: a benign brain tumour can compress vital brain centres.
Obstruction: a colonic polyp or bronchial adenoma may block a passage.
Hormone production: a pituitary adenoma may produce excess hormones.
Bleeding, ulceration, or rupture: depending on its site and size.

The NCI cancer overview similarly notes that benign tumours do not invade or spread, but can still cause serious symptoms in certain locations.

2. Malignant tumours

A malignant tumour is a neoplasm with the potential to invade local tissues and metastasise to distant organs.

Features

Cells can be well differentiated, poorly differentiated, or undifferentiated.
Growth may be rapid, but growth rate alone does not prove malignancy.
The mass is often irregular and poorly circumscribed.
It infiltrates and destroys nearby normal tissue.
It can recur after incomplete removal.
It may spread through lymphatics, blood vessels, or body cavities.
It can cause severe local damage, systemic illness, and death.

Examples

Tissue of origin	Malignant tumour
Squamous epithelium	Squamous cell carcinoma
Glandular epithelium	Adenocarcinoma
Bone	Osteosarcoma
Cartilage	Chondrosarcoma
Fat	Liposarcoma
Smooth muscle	Leiomyosarcoma
Blood-forming cells	Leukaemia
Lymphoid tissue	Lymphoma

3. Major differences

Feature	Benign tumour	Malignant tumour
Nature	Non-cancerous	Cancerous
Differentiation	Usually well differentiated	May be poorly differentiated or anaplastic
Cell appearance	Uniform, similar to normal cells	Pleomorphism, enlarged dark nuclei, abnormal mitoses may occur
Rate of growth	Usually slow	Variable, often faster
Margins	Well circumscribed, often encapsulated	Ill-defined and infiltrative
Local invasion	Absent	Present
Metastasis	Never occurs	May occur
Recurrence	Uncommon after complete removal	More common, especially if incompletely removed
Effects on patient	Usually local pressure or hormone effects	Local destruction, metastasis, cachexia, paraneoplastic effects

4. Differentiation and anaplasia

Differentiation means the extent to which tumour cells resemble their normal cells of origin in structure and function.

Benign tumours are generally well differentiated.
- Example: a lipoma contains cells closely resembling normal fat cells.
Malignant tumours may be well differentiated, but aggressive cancers are often poorly differentiated.

Anaplasia means lack of differentiation. It is a characteristic microscopic feature of many malignant tumours.

Features of anaplasia

Pleomorphism: variation in cellular and nuclear size and shape
Hyperchromasia: dark-staining nuclei due to increased DNA
High nuclear-to-cytoplasmic ratio
Large, prominent nucleoli
Numerous or atypical mitotic figures
Loss of normal tissue architecture
Tumour giant cells

5. Growth pattern and local invasion

Benign tumour growth

A benign tumour usually grows by expansion. It pushes surrounding tissues aside and may form a capsule from compressed connective tissue. Therefore, it is often easier to remove surgically.

Malignant tumour growth

A malignant tumour grows by infiltration and invasion. Cancer cells penetrate the extracellular matrix and basement membrane, then enter adjacent tissues. There is no true capsule, and tumour margins are often irregular.

Invasion is important because it:

Damages normal organs
Causes pain, bleeding, obstruction, and organ failure
Makes complete surgical removal difficult
Provides access to lymphatic and blood vessels

6. Metastasis

Metastasis means spread of malignant cells from a primary tumour to a distant, non-contiguous site, forming a secondary tumour. It is one of the strongest indicators that a tumour is malignant.

Benign tumours do not metastasise.

Main pathways

Lymphatic spread
- More common in carcinomas.
- Example: breast carcinoma spreading to axillary lymph nodes.
Haematogenous spread
- Common in sarcomas, but also occurs in carcinomas.
- Tumour cells enter blood vessels and commonly spread to the liver, lungs, bones, or brain.
Transcoelomic seeding
- Tumour cells spread across a body cavity.
- Example: ovarian carcinoma spreading throughout the peritoneal cavity.

The NCI SEER cancer terms resource describes malignant tumour spread through direct extension, lymphatic and blood vessels, or seeding in body cavities.

7. Why malignant tumours are life-threatening

Malignant tumours may cause death by:

Destruction of vital organs
Obstruction of airways, intestines, bile ducts, or urinary tract
Haemorrhage
Infection due to tissue breakdown or immunosuppression
Metastasis to organs such as the brain, liver, lungs, or bone marrow
Severe weight loss and muscle wasting, called cancer cachexia
Paraneoplastic syndromes, such as inappropriate hormone production or clotting disorders

Simple memory point

Benign = localised, non-invasive, non-metastatic.
Malignant = invasive, destructive, and potentially metastatic.

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