L29 - Etiology of Cancer and Interactions between Host and Tumor

What is Neoplasia?

Physiologically independent new growth that may be benign or malignant

What is the difference between a Benign and Malignant Neoplasm?

• Benign: does not invade surrounding tissues or metastasize

• Malignant: capable of local invasion and distant spread (metastasis)

What are the TWO key allmark features of Malignancy?

1. Local tissue invasion

2. Distant spread (metastasis)

What does “cancer” refer to in this lecture?

A malignant neoplasm

What is Hypertrophy?

An increase in cell size (or organ size)

What is Hyperplasia?

An increase in the number of cells

What is Metaplasia?

Altered differentiation of cells, usually in response to chronic inflammation

Why is Metaplasia concerning as a pre-malignant condition?

Cells experience altered differentiation and new growth signals

• If the insult persists, the persistent growth stimulus can favor neoplasia

What epithelial change is used as the example of Metaplasia?

Pseudostratified columnar → stratified squamous epithelium in response to chronic irritation/inflammation

What is Dysplasia?

Loss of architectural arrangement + increased cellular pleomorphism

Why is Dysplasia clinically important?

It is a significant pre-neoplastic lesion and can progress toward carcinoma in situ and carcinoma

What is Anisocytosis?

Variation in cell size and shape

What is Anisokaryosis?

Variation in nuclear size and shape

Easy way to remember Anisocytosis vs. Anisokaryosis?

• Cyto = cell → anisocytosis = variable cells

• Karyo = nucleus → anisokaryosis = variable nuclei

What does Homogeneous describe?

The entire population consists of one cell type

What does Heterogeneous describe?

The population contains multiple different cell types

What does Monomorphic mean?

Cells within a specific population have a similar appearance

What does Pleomorphic mean?

Cells within a specific population vary significantly in appearance

Homogeneous/Heterogeneous vs. Monomorphic/Pleomorphic — what is the difference?

• Homogeneous/heterogeneous: describes the entire cell population and number of cell types

• Monomorphic/pleomorphic: describes the appearance of cells within a specific population

Can a population be homogeneous AND pleomorphic?

Yes

• It can consist of one cell type whose individual cells vary greatly in size/shape.

Why can a Homogeneous, Pleomorphic tumor resemble a Heterogeneous population?

The same type of neoplastic cell can look very different, making it appear as though multiple cell types are present

Why is distinguishing Heterogeneous from Homogeneous-but-Pleomorphic populations clinically important?

It may help distinguish inflammation from neoplasia (cancer)

What may be needed when morphology alone cannot distinguish these populations?

• Special stains

• Immunohistochemistry

• Molecular diagnostics

What is Anaplasia?

Loss of features associated with normal cellular differentiation

Why is Anaplasia important when diagnosing tumors?

Highly anaplastic cells have lost their identifying features, making the tumor's cell/tissue of origin difficult to determine

What are the 3 Major Stages in the Development of Malignancy?

Initiation → Promotion → Progression

What occurs during Initiation?

Cell proliferation/replication results in a heritable mutation, creating an initiated cell

Is Initiation reversible or irreversible?

ALWAYS IRREVERSIBLE

Why is Initiation always irreversible?

Once the mutation becomes fixed through replication, the resulting cell carries the genetic alteration

What does irreversible initiation mean clinically?

Removing the original initiating cause does not remove the mutation already present in the initiated cell

What can initiate cells according to the lecture?

• Cell division/growth

• Environmental toxins

• Ionizing radiation

• UV radiation

What occurs during Promotion?

Growth signals favor proliferation of already-mutated/initiated cells

Is Promotion reversible or irreversible?

Reversible

What is the lecture's example of promotion?

Physiologic EGF preferentially promotes growth of the mutated cell

What is the clinical example showing that promotion can be reversible?

Spaying a dog removes estrus-associated promotion, reducing the growth stimulus

What occurs during Progression?

Promoted cells move toward malignancy through additional changes

How can Progression occur irreversibly?

Additional cell divisions → additional mutations → malignancy

How can Progression occur reversibly?

Inflammation → EGF release → promotes progression

• Reducing inflammation can delay this pathway

Which stage is ALWAYS irreversible?

INITIATION

• Promotion is reversible; progression can involve reversible or irreversible mechanisms

Quick way to distinguish Initiation, Promotion, and Progression?

→ Initiation = mutation

→ Promotion = growth of mutated cells

→ Progression = further changes toward malignancy

What is an Adenoma?

A benign epithelial neoplasm

What is Carcinoma in situ (CIS)?

A non-invasive epithelial neoplasm with cellular atypia but an intact basement membrane

Has carcinoma in situ invaded through the basement membrane?

No

• The basement membrane remains intact.

What distinguishes carcinoma from carcinoma in situ?

Carcinoma has invaded locally through the basement membrane

• CIS has not

Compare Adenoma → Carcinoma in situ → Carcinoma.

• Adenoma: benign

• CIS: marked atypia, but no invasion

• Carcinoma: malignant with local tissue invasion

What feature should you look for when deciding whether an epithelial tumor has become invasive carcinoma?

Invasion through the basement membrane into surrounding tissue

What is a Hamartoma?

Overgrowth of cells where they normally belong

What is the lecture's example of a Hamartoma?

Birthmark

What is a Choristoma?

Overgrowth of cells not normally present at that location

What is the lecture's example of a Choristoma?

Dermoid

What is a Teratoma?

A germ cell tumor containing tissues derived from endoderm, ectoderm, and mesoderm

Benign vs. Malignant SUMMARY

Feature	Benign	Malignant (Cancer)
Local invasion	No	Yes
Metastasis	No	Can occur
Key Concept	Remains non-invasive	Invades surrounding tissue ± spreads
Example	Adenoma	Carcinoma

Cell Morphology Vocabulary SUMMARY

Cyto = cell → anisocytosis
Karyo = nucleus → anisokaryosis

Term	What varies/is described?	Meaning
Anisocytosis	Cell	Variation in cell size & shape
Anisokaryosis	Nucleus	Variation in nuclear size & shape
Monomorphic	Specific cell population	Cells look similar
Pleomorphic	Specific cell population	Cells look different
Homogeneous	Entire population	One cell type
Heterogeneous	Entire population	Multiple cell types
Anaplasia	Differentiation	Loss of recognizable differentiated features

Homogeneous vs. Heterogeneous: Clinical Significance SUMMARY

	Heterogeneous	Homogeneous + Pleomorphic
Number of cell types	Multiple	One
Appearance	Cells look different because they are different types	Cells look different despite being the same type
Often suggests	Inflammation	Neoplasia
Why confusing?	Different cell types naturally look different	Tumor cells can vary dramatically in size/shape
If uncertain	Ancillary diagnostics	Ancillary diagnostics

Initiation vs. Promotion vs. Progression SUMMARY

Initiation = MUTATE → Promotion = MULTIPLY → Progression = MALIGNANT

	Initiation	Promotion	Progression
Key Concept	Mutation becomes fixed	Growth of initiated cells favored	Further changes → malignancy
Genetic?	Genetic	Genetic	Genetic and/or nongenetic
Reversible	ALWAYS irreversible	Reversible	Can be reversible or irreversible
Example	Mutagenesis during replication	EGF favors mutated-cell growth	Additional mutations or inflammation/EGF
Clinical significance	Mutation remains even if cause removed	Removing promoter can reduce growth stimulus	Drives population toward malignancy

Adenoma → Carcinoma in Situ → Carcinoma SUMMARY

Feature	Adenoma	Carcinoma in situ (CIS)	Carcinoma
Behavior	Benign	Non-invasive neoplasm	Malignant
Cellular atypia	Less severe	Present	Present
Basement membrane	Intact	Intact	Invaded
Local invasion	No	No	Yes
Key identifier	Benign epithelial tumor	Abnormal cells but no invasion	Abnormal cells but no invasion

Metaplasia → Dysplasia → Neoplasia SUMARY

Change	Main concept	Why care?
Metaplasia	Altered differentiation	Persistent growth cues may favor neoplasia
Dysplasia	Loss of architecture + ↑ pleomorphism	Significant pre-neoplastic lesion
CIS	Epithelial neoplasia, basement membrane intact	Non-invasive
Carcinoma	Invasion through basement membrane	Malignant