Principles and Practice of Human Pathology (NWIBB025B)
Institution
Radboud Universiteit Nijmegen (RU)
Detailed summary of the lectures in Principles and Practice of Human Pathology. The following lectures are included:
1.1 and 1.2 Pathology of Skin Tumours
1.7 and 1.8 Pathophysiology of Cervical Cancer
2.1 Anatomy and Physiology of the Endocrine System
2.2 Pathology of the Pituitary Gland
3...
Principles and Practice of Human Pathology (NWIBB025B)
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Monday, 25 January 2021
Pathology and Genetics of Skin Tumours
Human Pathology Lectures 1.1 and 1.2
Part 1: General principles of oncogenesis
- What is the difference between tumour and
neoplasm?
- Tumours refers to mass, which can grow due to inflammation. It can be neoplastic
or non-neoplastic.
- Neoplasm does not always form a mass, as it could also be blood-bound.
- Tumour/neoplasm does not always mean cancer, as the tumour could also be
benign or pre-malignant.
- Definition of neoplasia: ‘new growth of cells’, which is always genetically driven. It
can be benign, pre-malignant or malignant.
- Neoplasia examples: warts, moles, nevus. They are benign genetically driven
lesions.
- What is the difference between benign and malignant?
Benign neoplasm Malignant neoplasm
Only local growth (no invasion in other tissues) Invasion in other tissues
No metastases Can metastasize
Often slowly growing Often rapid growth due to cell proliferation,
leading to mitoses or even necrosis
Cells without cytonuclear atypia Cellular atypia
- Cytonuclear atypia: cells look less the
original cells as they have enlarged
nuclei > differences in nuclear form,
colour and size.
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- Cellular atypia in lung:
- Neoplasia is genetically driven. It is driven by genetic alterations, such as:
- Mutations
- Structural chromosomal alterations: translocation or gene fusions.
- Copy number variations: losses or gains of parts or whole chromosomes.
- Viral transformation: viral DNA gets incorporated into the cell.
Mutation is a nucleotide change in DNA or a change in the DNA sequence. There
are different types of mutations:
- Substitution: when a nucleotide is replaced
by another nucleotide, resulting in the
substitution of the amino acid and then
change in the protein sequence.
- Insertion: of one or more nucleotides, which
leads to out-of-frame mutations. This
changes the sequence of the protein. Then
an inactivated or ineffective protein is
created.
- Deletion: one of a few nucleotides are
deleted. This leads to an out-of-frame
mutation and thus a non-sense sequence.
- Copy number variations: losses or gains of
whole chromosomes or part of chromosomes.
- Structural variations: when there are translocations > parts of, for example,
chromosome 3 is translocated to chromosome 9.
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3 types of genes can be involved in oncogenesis (oncogenesis only occurs when
the genes affected are involved in oncogenesis):
1. (Proto)oncogenes: main function is to promote cell proliferation and survival.
When a mutation or amplification occurs, it leads to a gain of function, activation
or over expression. This promotes more cell proliferation and survival.
2. Tumour suppressor genes: main function is to inhibit cell proliferation and
induction of apoptosis. When there is a mutation in of these genes, there will be
inactivation or loss of function of the tumour suppressor gene. This then leads to
the loss of induction of apoptosis and loss of inhibition of cell proliferation.
3. Mutation / mismatch repair genes: main function is to repair DNA replication
errors. When there is a mutation in of the genes leading to loss of function
results in an accumulation of DNA errors.
Mutations can be somatic or germ-line:
a) Somatic mutations: acquired during life, present only in certain cells of the
body and they are dependent on the cause of the mutation. For example: UV
induced TP53 mutations in epithelial cells of the skin. Mutations due to smoking
mostly only affect epithelial cells of the lung. Mutations occur later in life and are
only present in one place of the body.
b) Germ-line mutations: hereditary,
congenital, present in all cells of
the body; already present in the
fertilised egg > disturbed to all
cells of the body
Benign neoplasia’s usually have
simple genetic alterations:
- Most common nevi (moles) have
only one mutation > 60% BRAF,
20% NRAS
- Spitz nevi (non-pigmented moles in children) only have one chromosomal
translocation in one of the oncogenes: ALK, ROS of NTRK translocation.
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- Some Spitz nevi have both one HRAS mutation and one gain of chromosome
11p. No other mutations.
Cancer is a multistep process: clonal evolution model
- Cancer occurs when there are several mutations (at least 6) in different genes
controlling cell growth, differentiation and death.
- It starts with a precancerous genetic change (only one change, such as in nevi)
- Then additional genetic changes leads to cancerous growth. These changes
leads to
- Autonomous cell proliferation
- Loss of cell contact inhibition: invasion occurs
- Development of new vessels so that cancer can
grow
- Growth into lymph vessels (metastasis)
- Clonal evolution model: every time a new mutation
in one the cells, there is a clone of this cell within the
tumour. This clone will have a proliferation or
survival advantage over the rest of tumour. Every
time there is a new mutation, this mutation will have an advantage over the rest of
the cells.
- The tumour that can grow out and metastasise usually have all the different
mutations.
Part 2: Skin cancer
Skin cancer is the most common primary location of cancer
- Incidence of skin cancer is rising very fast
- Why is the frequency so high? Skin is our largest organ and there is life long
exposure to UV radiation
Different mutational processes generate unique combinations of mutation types,
named ‘mutational signatures’.
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