Download Basic Science of Oncology

Basic Science of Oncology
Objectives
The following module was designed to supplement medical students’ learning in the clinic. Please take
the time to read through each module by clicking the headings below. Information on the molecular
biology, pathology, and anatomy of basic oncology is discussed. The content of this module is mirrored to
the objectives listed by the 2015 Canadian Oncology Goals and Objectives for Medical Students (by the
Canadian Oncology Group).
By the end of the tutorial, the following objectives should be addressed:
Molecular Biology
1. Describe in general terms how cancers develop and be able to describe the hallmarks of cancer.
2. Describe the step-wise progression from normal to pre-malignant to malignant histology and how
this relates to the principles of screening and early detection.
3. Demonstrate an understanding of how hormones influence development of certain cancers and
how this may help direct management.
4. Describe the important genetic/familial syndromes related to cancer development, identify their
mode of inheritance and impact on cancer development.
5. Describe how common carcinogens can cause cancer (e.g. cigarette smoke, asbestos, UV
radiation, radiation exposure).
6. Describe how common infections can cause cancer (e.g. viral hepatitis, H. pylori, EBV, HPV, HIV).
Pathology
1. Define the terms metaplasia, dysplasia, carcinoma, sarcoma, lymphoma, leukemia and germ cell
tumour.
2. Describe the histologic differences between benign and malignant tumors.
3. Demonstrate an understanding of common pathological terminology used in cancer diagnosis
(e.g. stage, grade).
4. Describe the importance of tissue sampling for diagnosis of malignancy and for identification of
molecular predictive factors.
5. Demonstrate an understanding of the differences between fine needle aspiration biopsy, core
biopsy, and surgical excision.
6. Demonstrate an understanding of the role of different specialists in obtaining a tissue diagnosis
of cancer (e.g. family physician, hematologist, radiologist, surgeon, oncologist).
Anatomy
1. Describe the most common patterns by which cancer spreads (i.e. direct extension, lymphatic,
hematogeneous, transcelomic).
2. Demonstrate an understanding of relevant anatomy for common cancers (i.e. prostate, breast,
lung and colorectal cancers) in terms of how they invade and metastasize, with an emphasis on
invading adjacent structures, spread through the lymphatic and vascular systems.
Major Contributors
Tim Kong – Medical Student
Paris Ann-Ingledew – MD, FCRP Radiation Oncologist
Section 1: Molecular Biology
What is cancer?
Cancer is a disease where cells lose normal growth regulation, proliferate abnormally from their normal
counterparts, and invade other tissues. Often, it is not a single disease but a collection of multiple cellular
abnormalities. Cancer cell behaviour is differentiated from normal cells by four characteristics (Table 1):
Table 1. Four hallmarks of cancer cells
Characteristic Definition
Clonality
One cell leads to the proliferation of many malignant cells
Autonomy
Growth is resistant to normal regulation
Anaplasia
Cell differentiation is less or not at all coordinated
Metastasis
Malignant cells disseminate and grow discontinuously to other parts of the body
These four characteristics may actually exist in normal, non-cancerous cells. However, this dysregulation
is inappropriate and excessive in cancer (1). Additional hallmarks exist to further specify the types of
cellular dysfunction from the four characteristics above (figure 1).
Figure 1. Abnormal cellular hallmarks which are excessive in cancer cells
Terms to describe tumor and cancer development
Many terms exist to classify cell dysregulation and can describe how cells can develop into cancer. It is
important to note that not all these terms are synonymous with the disease of cancer itself (Table 2).
Table 2. Tumors and cancers describe different aspects of cellular dysfunction
Term
Tumor
Definition
 Abnormal mass of tissue which results from:
i. Excessive cell division
ii. Evasion of apoptosis (reduced cell death)
 Can be benign or malignant
 Equivalent to the term neoplasm
Cancer
 Disease consisting of:
i. Deregulated cell growth (the 4 characteristics mentioned above)
ii. The ability to invade other organs and tissue
 Cancer is automatically malignant
The terms benign and malignant describe a property of cells which have abnormal cell growth and
proliferation (Table 3). Both terms refer to cells which have lost normal regulation of cell division and
death. However, only malignant cells possess the ability to spread and invade other tissues.
Table 3. Tumors may be benign or malignant, and may have the potential to spread
Benign




Malignant
 Cells are cancerous
 Cancerous cells can spread and invade other tissues
Metastasis
 The process and outcome of malignant or cancerous cells spreading and invading
Cells are not cancerous
Local problems; does not spread
Most growths do not return when removed
For example: benign thymomas, acoustic neuromas
other tissues
In most literature and in this module itself, several equivalent terms will be used interchangeably. Tumor
and neoplasm both refer to abnormal, unregulated growths of tissues. Malignant tumor, malignancy, and
cancer all refer to the invasive nature and disease of abnormal, unregulated growths of tissues.
Step-wise progression of cancers
Genetic abnormalities cause the vast majority of human cancers (1). Mutations in genetic material are
caused by variety of etiologies such as damaging radiation, exposure to carcinogens, or failure in proofreading mechanisms. These abnormalities result in loss of regulation over cell growth and proliferation.
Abnormal cell growth behaviour is often reversible (Table 4). That is, they are caused by a stimulus and
are ceased when the stimulus is removed.
Table 4. Abnormal proliferative growth behaviour may be reversible with removal of the stimulus
Term
Definition
Hyperplasia
 Increase in number of cells within an organ or tissue
Hypertrophy
 Increase in size of cells within an organ or tissue
Atrophy
 Reduction of cell size or number
Pre-malignant changes in cells are referred to as dysplasia, and is seen as dysfunctional cell growth and
morphological changes in cell nuclei (2). Dysplasia results in cells losing specific characteristics from their
tissue of origin. This loss in cellular differentiation is classified as grades (low, medium, and high) where
lower grade neoplasms resemble their tissue of origin better than higher grade neoplasms. It is
important to remember that dysplasia are not necessarily cancers; they simple describe the growth
pattern of a neoplasm, which can either be benign or malignant. Metaplasia is the reversible
replacement of one cell type by another (2). Like dysplasia, metaplasia are not necessarily cancers and
may be reversed upon removal of a certain stimulus. One example of a benign metaplasia is the
transformation of respiratory epithelium from columnar to squamous type due to chronic irritation like
smoking.
Transformation of normal to pre-malignant to malignant cells follows a course of step-wise histological
changes (Figure 2). In epithelium, normal cells initially undergo low to medium grade dysplasia due to a
stimuli such as a genetic abnormality. This initial dysplasia does not involve the entire epithelial height
and is not cancerous. It can either revert back to normal or progress to high grade dysplasia. Should it
progress, the dysplastic cells can involve the entire epithelial thickness and accumulate to push against
the underlying basement membrane (Table 5). Penetration through the basement membrane would
allow the neoplasm to invade other tissues, thus deeming it cancerous.
Table 5. The intactness of the basement membrane dictates neoplasm invasiveness
Term
Definition
Carcinoma
in situ
 Dysplastic cells involve the entire epithelial thickness and push against the
Malignant
neoplasm
 Dysplastic cells have broken past the basement membrane
 Cells are invasive as the basement membrane is no longer intact
basement membrane
 Equivalent term to high grade dysplasia
 Pre-malignant; non-malignant (non-invasive) because the basement membrane is
still intact
Figure 2. Normal epithelium progresses to pre-malignant and malignant states through dysplasia
By these definitions, dysplastic cells are not malignant and cannot disseminate to other tissues until the
basement membrane is broken. Thus, carcinomas in situ are not malignant and are technically benign
neoplasms. However, carcinomas in situ are automatically high-grade dysplasia and its cells have the
potential to become malignant. Consequently, most carcinomas in situ eventually progress to malignant
carcinoma.
Hormones influence the development of cancer
Hormones act as stimuli which influence cancer development in tissues such as the breast, endometrium,
ovary, prostate, testes, thyroid, and bone. Endogenous and exogenous hormones regulate cell growth
and proliferation at normal levels. Increased hormone levels can lead to excessive cell proliferation which
can accumulate genetic abnormalities (3).
Breast cancer is the most common cancer in women, and is driven by hormones. Germline mutations in
breast epithelial cells, such as those in the BRCA1 gene, predisposes cells to genetic mutations (3).
Estradiol (or estrogen) produced in the ovaries further drives cell proliferation and following the cell
proliferation model, leads to an accumulation of genetic abnormalities. Eventually, these abnormalities
produce a malignant phenotype consistent with breast cancer.
Hormone driven cancers can be managed by controlling endogenous hormone levels. Hormonal
anticancer pharmacotherapy is currently a major method of control. Examples include hormonal
antagonists to block target receptors, or hormonal analogues which mimic hormones and induce negative
feedback reduction of hormone production. Pharmacotherapy can also block enzymes in hormone
synthesis pathways such as aromatase inhibitors required for estrogen production (3). Surgical removal
of the hormone-producing organ is the final option in hormone therapy. Thus, hormone therapy is a
specific form of treatment and can be used to predict treatment success in certain cancers. For example,
estrogen and progesterone receptor statuses direct the management algorithm in breast cancer.
Various molecular markers exist to indicate the presence of cancer. These markers mainly aid diagnosis
and assess prognosis (2). As well, the presence of certain markers offer insight into possible treatment.
For example, hormone epidermal receptor 2 proteins (HER2) are present in approximately one-fifth of
breast cancers (6).
Familial and genetic syndromes are related to cancer development
Family history is a major determinant of risk for developing and having certain cancers. However, it is
interesting that only five percent of cancers have hereditary relationships. The two-hit hypothesis
explains the increased genetic predisposition in patients with a positive family history. Various genes exist
in the body to suppress cancer development. One example is a type called the tumor suppressor gene.
Recall that genes in a cell exist as two copies (two alleles) with one copy from each parent. Thus for a
cancer to develop, two hits are required to compromise both alleles and cause cancer. Patients with a
hereditary syndrome have one hit already, and are born with only one normal allele. They are predisposed
to cancer since they only require one additional hit to result loss of both genes.
Figure 3. Familial or hereditary syndromes result in genetic predisposition of cancer development
Carcinogenic mechanisms
Carcinogens are substances which induce malignancy by altering normal cellular genetics. They can be
classified in three general categories: chemicals, radiation, and viruses. Chemicals and radiation cause
biochemical damage and alterations to normal DNA. Common chemical carcinogens include cigarette
smoke and asbestos, and common radiation carcinogens include UV radiation from the sun and radiation
therapy. Viruses act differently by introducing new genetic material to a cell. The new genetic material
may alter existing genetic material leading recombination which may be malignant (5).
Section 2: Pathology
Staging vs. Grading
Staging and grading of cancers are different classification methods. The grade of a neoplasm refers to
the histological and pathological features of the cells in a neoplasm. Recall that dysplasia is the
abnormal proliferation of deregulated cells. As dysplasia develops, the neoplastic cells lose features of
their tissue of origin, become less differentiated, and are presumed to be of higher grade.
The stage of a neoplasm provides a sense for how advanced a cancer is. Many (but not all) cancers are
staged using the TNM staging system. This system is divided into three components: the tumor (T),
nodal status (N), and metastasis (M), universally called the TNM staging system (Table 6). The TNM
status will be different for each patient depending on their tumor and cancer. Different combinations
can further be classified into general stages I, II, III, IV. We stage cancers for the following reasons: it
provides a common language of communication, guides treatment, estimates prognosis, allows
comparison of results, and standardizes clinical trials. Stage I cancers are early cancers that are often
curable. Stage IV cancers are usually incurable. The TNM and staging differ for each tissue of origin and
thus, specifically predict the management and prognosis of individual cancers (2).
Table 6. TNM staging provides a universal classification of tumor description
Component
Definition
Tumor (T)




Node (N)
 Absence or presence of malignancy in the regional lymph nodes
 N 0 refers to absent nodal malignancy
 N 1,2,3 represent the extent of nodal involvement
Metastasis (M)
 Absence or presence of metastasis
 M 0 represents no metastasis
 M 1 represents metastasis
Extent of local, primary tumor growth
TIS refers to carcinoma in situ
T 1,2,3,4 represent the size and extent of the local, primary tumor
T 0 refers to no primary tumor
Biopsies for diagnosis
Confirmatory diagnosis of cancer often requires direct histological analysis of tissue. Obtaining a biopsy
is the process of removing and examining tissue, and is performed through various methods. With
cancer, suspicious regions of tissue are often biopsied for analysis; these could include abnormal lumps
or regions identified by imaging.
Fine needle aspiration biopsy uses a fine needle and syringe sample a tissue. Negative pressure through
suction provides the force to remove the tissue. Deep tissues such as the lungs or liver may require
radiological guidance. Biopsies with simpler imaging modalities such as ultrasound may be performed in
a non-specialist's clinic. However, more complicated procedures may require a radiologist or trained
surgeon in the hospital. Superficial tissues such as the prostate or breast do not require additional
guidance (7).
Core biopsy uses a larger cylindrical needle and extracts cylinders, or cores, of tissue. This provides a
larger sample of tissue to analyze than fine needle aspiration biopsies. Similarly, simple procedures may
be performed in the office setting by a non-specialist (7).
Surgical biopsy involves extracting large amounts of tissue. There are two types of surgical biopsy:
incisional and excisional. Incisional surgical biopsies removes parts of abnormal tissue, similar to fine
needle and core biopsies but in a larger amount. Excisional surgical biopsies removes the entire
abnormal area or tumor, and may additionally excise normal tissue around it. Excisional biopsies may
very well be curative intents to remove affected parts of an organ or the entire organ itself, with tissue
analysis following the excision. Surgical biopsies are typically performed in the hospital with local or
general anesthesia depending on the extent of analysis (7).
Section 3: Anatomy
Spread of cancer
Benign tumors grow slowly, resemble the tissue of origin, and do not invade other tissues. Thus, benign
tumors are localized and can be cured by removal. Some benign tumors may develop into malignant
tumors (cancer), which grow much faster, do not resemble the tissue of origin, and invade other tissues.
Malignant tumors metastasize and spread to other parts of the body, making them more dangerous and
less curable (2).
Cancer spread is classified into three mechanisms: local, lymphatic, and hematogenous spread. The TNM
staging mimics these three patterns of spread.
Local spread is the spread of a cancer within an organ or structure. The cancer is still considered malignant
since it has likely broken the basement membrane and has disseminated within intra-organ passages. The
tumor may now exist as a direct extension of the original tumor, or appear as multiple, discrete tumors
throughout the organ (2). This corresponds with the T stage of the TNM.
Recall that the lymphatic system is a network of circulatory vessels to collect and redistribute excess fluid
in the body. Superficial channels in the skin and subcutaneous tissues drain into deeper channels which
ultimately collect into large ducts that drain into the vascular system. Along the way are lymph nodes,
which are accumulations of lymphoid tissue, which play a role in the immune system. Lymphatic invasion
correlates with the N stage of the TNM.
Cancers often disseminate into the lymph pathways and follow the drainage of lymph into lymph nodes.
This may allow detection and localization of cancers through physical exam, as cancerous lymph nodes
are often hard, tender, and matted-down. For example, cancer in the outer breast spreads to ipsilateral
axillary lymph nodes, while cancer in the inner breast spreads to the internal mammary chain lymph nodes
(Figure 4).
Figure 4. Lymphatic spread of cancer involves dissemination through lymph drainage around the breast (8)
Hematogenous spread of cancer follows the vascular circulation of blood. Metastases from organ to organ
almost always requires hematogenous spread. Cancers may simply follow the path of circulation, such as
gastrointestinal cancers spreading to the liver via the portal vein. However, cancers may also directly
invade a vessel such as a renal cancer spreading into the renal veins. Tumors often invade veins but rarely
invade arteries (2).
References
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2.
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4.
5.
6.
Isselbacher K, Harrison T. Harrison's principles of internal medicine. New York: McGraw-Hill; 1995.
Shah A. Essentials of clinical oncology. Vancouver: Somerset Pub.; 2004.
Henderson B. Hormonal carcinogenesis. Carcinogenesis. 2000;21(3):427-433.
Schwartz S. Principles of surgery. New York: McGraw-Hill, Health Professions Division; 1999.
Murray R. Harper's illustrated biochemistry. New York: McGraw-Hill Medical; 2012.
Uptodate.com. Adjuvant medical therapy for HER2-positive breast cancer [Internet]. 2015 [cited
17 June 2015]. Available from: http://www.uptodate.com/contents/adjuvant-medical-therapyfor-her2-positive-breastcancer?source=search_result&search=her+2+breast+cancer&selectedTitle=1~150
7. Cancer.org. Types of biopsy procedures [Internet]. 2015 [cited 19 June 2015]. Available from:
http://www.cancer.org/treatment/understandingyourdiagnosis/examsandtestdescriptions/forwo
menfacingabreastbiopsy/breast-biopsy-biopsy-types
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http://www.cancer.org/cancer/breastcancerinmen/detailedguide/breast-cancer-in-men-what-isbreast-cancer-in-men