Principles and Practice of
Human Pathology
Week 1: Monday 31st January
L.C. 1.1
Neoplasia
Neoplasm: genetically drive growth of cells (benign, pre-malignant, malignant)
Tumor vs neoplasm: they’re not exactly the same. A tumor is the formation of a mass (can
be due to genetical background and can also grow due to inflammation). A neoplasm does
not always cause a mass (leukemia)They can both be benign or malignant.
Benign neoplasm Malignant neoplasm
often slowly growing, often rapid
only local growth infiltration in other tissues
no metastasis (migration through lymph can metastasize
nodes)
cells without atypia (ex. a moll) atypical cells (do not look like their
precursor cells)
The development of cancer: usually at least 6 genes are involved
- Autonomous cell proliferation: growth
- New vessels formation: growth
- Loss of programmed cell death: growth survival
- Loss of differentiation: loss of function
- Loss of cell contact inhibition: invasion
- Growth into and out of vessels: metastasis
Within the tumor you can find different clones with different mutations.
Genes:
1. (proto)oncogenes: involved in promotion of cell growth gain of function =
activation/gain of expression
2. Tumor suppressor genes: inhibition of cell proliferation or induction of apoptosis
loss of function mutation/loss of gene/loss of expression (happens in both alleles)
3. DNA repair genes: control of genome/repair of DNA replication errors loss of
function/loss of gene/loss of expression
4. Viral genes (usually acting as oncogenes, but it’s not sure)
,3 types pf genetic alterations:
1. Mutations: small nucleotide change in DNA. (substitution, insertion, deletion)
activation of oncogenes or loss of function/expression of tumor suppressor genes,
frameshift leads to loss of function while no frameshift leads to gain of function
2. Copy number variations: gains of oncogenes, loss of tumor suppressor genes
3. Chromosomal alterations: expression or activation of oncogenes
Mutations in cancer:
Somatic mutation: acquired, present only in certain cells of the body, dependent on
carcinogen: e.g., UVB. Induced TP53 mutation in epithelial cells of the skin
Germline mutations (often family history): congenital, present in all cells of the body, can
give susceptibility for cancer.
Skin Cancer
Skin cancer is rising very fast.
Causes: the fact that the skin is the biggest organ, aging, life long exposure to UV light,
tanning beds, viral infections (HPV), hereditary reasons
Mutational signature of UV light: CCTT
Clinical Pathology
Clinical pathologist: medical specialist who diagnoses disease by investigating tissues and
cells of patients
Pathological investigation of skin tumor:
1. Assessment of line of differentiation: from which tissue/cells is the tumor derived?
2. Establish whether tumor is benign or malignant diagnosis
3. Determine the stage of the tumor (invasion depth)
4. Establish whether the margins are free of tumor
Pathological examination determines clinical management
Diagnosis, stage and margins determine: necessity of excision, margins of excision, adjuvant
radiotherapy, sentinel node excision, adjuvant systemic therapy
Bread loafing is a common method of processing surgical specimens for histopathology. The
process involves cutting the specimen into 3 or more sections. The cut sections are mounted
by embedding in paraffin or frozen medium. The cut edge is then thinly sliced with a
microtome or a cryostat.
Diagnosis of tumor:
- Routine histology (H&E staining, nucleus is stained purple and the rest pink)
- Immunohistochemistry (usage of an antibody directed against an antigen on a tumor
cell. The binding is subsequently visualized with a chromogen)
, - Molecular pathology (to determine treatment options)
L.C 1.2
Different skin tumors:
Skin cancer is NOT once cancer because the skin contains different kind of structures that
give rise to different cells
Basal Cell Carcinoma (BCC): by far the most common
skin cancer, it’s becoming epidemic
- Derived from hair follicle
- Locally aggressive, can be mutilating, hardly ever
metastasizes
- Only in skin, frequent around eyes and nose, not
found on mucosa, palms and soles
- Marker: Ber-EP4
Histology: very dark nuclei with little cytoplasm, empty
space around tumor margins
Etiology: UVB (age mostly, Caucasians, UV specific mutations, sun exposure)
Squamous Cell Carcinoma (SCC):
- Derived from epidermis/keratinocytes
- Mutilating,
- Mostly in areas with cumulative sun exposition
- Can metastasize (mostly nodal)
- Marker: P63
Etiology: UVB (sun exposed sites and UV specific mutations), HPV (especially in immune
compromised patients)
It often occurs after precancerous lesions/dysplasia
Actinical keratosis (sun damage leading to formation of horns) caused by UVB
Morbus Bowen (larger with better margins, hypertrophic epidermis, irregular nuclei,
no invasive growth) caused by HPV
, Melanocytic Tumors
Melanocyte: pigment producing cell, basal layer in the epidermis, 1 melanocyte
communicates with 30-40 keratinocytes (protection from UV light)
Origin: megaloblasts (precursors) are present in the neural crest for more that 8 weeks after
fertilization. Melanoblasts mostly migrate to the epidermis and hair follicles and a few
migrate to the eye, inner ear and brain.
Melanocyte number is the same in all skin colors (it’s the amount of melanin that changes)
BENIGN
Common acquired melanocytic nevus
marker: s100
- Develop mostly in the first 2 years of life
- Most people have 20-30 common nevi
- 60% BRAFV600E mutations, 20% NRASQ61R mutations
Junction nevus: in the basal layer of the epidermis (between the epidermis and the
dermis)
Dermal nevus: small cells with rounded nuclei, no atypia, no enlargement, no mitosis
Spitz nevus: uncommon type, face and extremities of children and young adults,
rapid growth in months, dome shaped nodule, papule, symmetrical lesion, large cells and
nuclei, possible mitosis. Formed by translocation in tyrosine kinase receptors.
NTRK staining indicates the translocation.
Driven mutations in oncogenes
- Early initiating mutations in tumors
- Present in benign tumors
- Stay present in case of malignant progression
- Hotspot mutations
- Leading constant activated state of the oncogene
- Constant activation of the pathway
Most common oncogenes: BRAF, NRAS, HRAS, KIT, GNAQ, GNA11
BRAG is continuously activated without the need for a ligand in the MAPK/ERK pathway.
Human Pathology
Week 1: Monday 31st January
L.C. 1.1
Neoplasia
Neoplasm: genetically drive growth of cells (benign, pre-malignant, malignant)
Tumor vs neoplasm: they’re not exactly the same. A tumor is the formation of a mass (can
be due to genetical background and can also grow due to inflammation). A neoplasm does
not always cause a mass (leukemia)They can both be benign or malignant.
Benign neoplasm Malignant neoplasm
often slowly growing, often rapid
only local growth infiltration in other tissues
no metastasis (migration through lymph can metastasize
nodes)
cells without atypia (ex. a moll) atypical cells (do not look like their
precursor cells)
The development of cancer: usually at least 6 genes are involved
- Autonomous cell proliferation: growth
- New vessels formation: growth
- Loss of programmed cell death: growth survival
- Loss of differentiation: loss of function
- Loss of cell contact inhibition: invasion
- Growth into and out of vessels: metastasis
Within the tumor you can find different clones with different mutations.
Genes:
1. (proto)oncogenes: involved in promotion of cell growth gain of function =
activation/gain of expression
2. Tumor suppressor genes: inhibition of cell proliferation or induction of apoptosis
loss of function mutation/loss of gene/loss of expression (happens in both alleles)
3. DNA repair genes: control of genome/repair of DNA replication errors loss of
function/loss of gene/loss of expression
4. Viral genes (usually acting as oncogenes, but it’s not sure)
,3 types pf genetic alterations:
1. Mutations: small nucleotide change in DNA. (substitution, insertion, deletion)
activation of oncogenes or loss of function/expression of tumor suppressor genes,
frameshift leads to loss of function while no frameshift leads to gain of function
2. Copy number variations: gains of oncogenes, loss of tumor suppressor genes
3. Chromosomal alterations: expression or activation of oncogenes
Mutations in cancer:
Somatic mutation: acquired, present only in certain cells of the body, dependent on
carcinogen: e.g., UVB. Induced TP53 mutation in epithelial cells of the skin
Germline mutations (often family history): congenital, present in all cells of the body, can
give susceptibility for cancer.
Skin Cancer
Skin cancer is rising very fast.
Causes: the fact that the skin is the biggest organ, aging, life long exposure to UV light,
tanning beds, viral infections (HPV), hereditary reasons
Mutational signature of UV light: CCTT
Clinical Pathology
Clinical pathologist: medical specialist who diagnoses disease by investigating tissues and
cells of patients
Pathological investigation of skin tumor:
1. Assessment of line of differentiation: from which tissue/cells is the tumor derived?
2. Establish whether tumor is benign or malignant diagnosis
3. Determine the stage of the tumor (invasion depth)
4. Establish whether the margins are free of tumor
Pathological examination determines clinical management
Diagnosis, stage and margins determine: necessity of excision, margins of excision, adjuvant
radiotherapy, sentinel node excision, adjuvant systemic therapy
Bread loafing is a common method of processing surgical specimens for histopathology. The
process involves cutting the specimen into 3 or more sections. The cut sections are mounted
by embedding in paraffin or frozen medium. The cut edge is then thinly sliced with a
microtome or a cryostat.
Diagnosis of tumor:
- Routine histology (H&E staining, nucleus is stained purple and the rest pink)
- Immunohistochemistry (usage of an antibody directed against an antigen on a tumor
cell. The binding is subsequently visualized with a chromogen)
, - Molecular pathology (to determine treatment options)
L.C 1.2
Different skin tumors:
Skin cancer is NOT once cancer because the skin contains different kind of structures that
give rise to different cells
Basal Cell Carcinoma (BCC): by far the most common
skin cancer, it’s becoming epidemic
- Derived from hair follicle
- Locally aggressive, can be mutilating, hardly ever
metastasizes
- Only in skin, frequent around eyes and nose, not
found on mucosa, palms and soles
- Marker: Ber-EP4
Histology: very dark nuclei with little cytoplasm, empty
space around tumor margins
Etiology: UVB (age mostly, Caucasians, UV specific mutations, sun exposure)
Squamous Cell Carcinoma (SCC):
- Derived from epidermis/keratinocytes
- Mutilating,
- Mostly in areas with cumulative sun exposition
- Can metastasize (mostly nodal)
- Marker: P63
Etiology: UVB (sun exposed sites and UV specific mutations), HPV (especially in immune
compromised patients)
It often occurs after precancerous lesions/dysplasia
Actinical keratosis (sun damage leading to formation of horns) caused by UVB
Morbus Bowen (larger with better margins, hypertrophic epidermis, irregular nuclei,
no invasive growth) caused by HPV
, Melanocytic Tumors
Melanocyte: pigment producing cell, basal layer in the epidermis, 1 melanocyte
communicates with 30-40 keratinocytes (protection from UV light)
Origin: megaloblasts (precursors) are present in the neural crest for more that 8 weeks after
fertilization. Melanoblasts mostly migrate to the epidermis and hair follicles and a few
migrate to the eye, inner ear and brain.
Melanocyte number is the same in all skin colors (it’s the amount of melanin that changes)
BENIGN
Common acquired melanocytic nevus
marker: s100
- Develop mostly in the first 2 years of life
- Most people have 20-30 common nevi
- 60% BRAFV600E mutations, 20% NRASQ61R mutations
Junction nevus: in the basal layer of the epidermis (between the epidermis and the
dermis)
Dermal nevus: small cells with rounded nuclei, no atypia, no enlargement, no mitosis
Spitz nevus: uncommon type, face and extremities of children and young adults,
rapid growth in months, dome shaped nodule, papule, symmetrical lesion, large cells and
nuclei, possible mitosis. Formed by translocation in tyrosine kinase receptors.
NTRK staining indicates the translocation.
Driven mutations in oncogenes
- Early initiating mutations in tumors
- Present in benign tumors
- Stay present in case of malignant progression
- Hotspot mutations
- Leading constant activated state of the oncogene
- Constant activation of the pathway
Most common oncogenes: BRAF, NRAS, HRAS, KIT, GNAQ, GNA11
BRAG is continuously activated without the need for a ligand in the MAPK/ERK pathway.
