Neoplasia
Neoplasia is the uncontrolled, abnormal growth of cells or tissues in the body, and the abnormal growth itself is called a neoplasm (Greek;
neo=new, plasma=thing formed), the autonomous growth of tissues that have escaped normal restraints on cell proliferation, and exhibit
varying degrees of fidelity to their precursors.
Stochastic factors are determined by chance.
Growth disorders can be classified into: The cells gradually acquire genetic changes in
- Reactive growth disorders: mostly reversible in nature. Examples are hyperplasia and proto-oncogenes and tumor suppressor genes.
metaplasia. Accumulation of genetic changes underlies the
transformation of a normal cell into a cancer
Dysplasia may be reversible, but will often result in a neoplasm belonging to the autonomic growth cell. The chance of suffering from a malignant
disorders which are irreversible. tumor therefore increases with age. This is
In metaplasia there is an increased chance of developing a neoplasm as a result of dysplasia. This why, in the past, when the average life
expectancy was barely 40 years, people
shows that the development of malignant tumors is a gradual process in which stochastic factors suffered far less frequently from cancers.
play a role.
Mutations can be somatic or germline. Somatic mutations is acquired and
- Autonomic growth
present only in certain cells of the body, dependent on the cause. Germline
disorders mutations are hereditary, congenital and present in all cells of the body.
Tumors occur often and may be either benign or malignant in nature.
This classification is based on the difference in their clinical-biological behavior. Cancer is a collective
name for all malignant tumors and is the main cause of death in the Western world after cardiovascular
disease.
Benign tumors do not penetrate (invade) adjacent tissue borders, nor do they spread (metastasize) to
distant sites. These cells often grow slowly and show no atypia.
Malignant tumors have a property of invading contiguous tissues and metastasizing to distant sites,
where subpopulations of malignant cells take up residence, expand and again invade. These cell can
have rapid growth by mitoses and necrosis. There is cellular atypia.
HPV is a DNA virus that infects
squamous epithelium. There are
Neoplasia is genetically driven by genetic alterations: 170 types of which 40 genital
- Mutations (a nucleotide change in DNA): Substitution, transmitted, the different types
Insertion, Deletion of HPV cause different
neoplasms. Also squamous cell
- Structural chromosomal alterations: translocation/gene fusions carcinoma of the skin can be
- Copy number variations: losses or gains of parts or whole caused by HPV in
chromosomes immunocompromised patients.
- Viral transformation
Benign neoplasia’s usually have simple alterations.
Most common nevi (moles) have only one mutation. 60% BRAF, 20% NRAS
Spitz nevi (non-pigmented moles in children) have one chromosomal translocation ALK, ROS of NTRK translocation
Some spitz nevi have one HRAS mutation and one gain of chromosome 11p.
Cancer is a multistep process and is described as the clonal evolution model. Several mutations in different
genes controlling cell growth, differentiation and death. Often starting with a precancerous genetic change.
Additional genetic changes lead to cancerous growth like Autonomous cell proliferation, Loss of cell contact
inhibition: invasion occurs, New vessels develop, Growth into vessels and metastasis can occur
Skin is the most common primary location of cancer because the skin is our largest organ and we have a
lifelong exposure to UV light.
Different mutational processes generate unique combinations of mutation types, termed mutational signatures. Mutational signatures are
characteristic combinations of mutation types arising from specific mutagenesis processes.
Pathological examination
Depending on diagnosis of skin biopsy a skin excision is performed where together with a safety
margin of normal skin the neoplasm is removed.
Tissue samples collection and/or cell isolation → tissue processing phase including fixation,
dehydration, infiltration and embedding in paraffin → sectioning with microtome followed by
mounting on microscope slides → clearing and staining.
Assessment of origin: from which tissue/cells is the tumor derived (what does it look like)
Establish whether the tumor is benign or malignant (atypia, mitoses, necrosis, invasion). By these two a
diagnosis is made.
Depending on diagnosis a skin excision is made. Pathologists use broad leaf technique for lamination
material so they can make representative cuts through the tumor. And can see how deep the tumor
grows, whether the cutting planes are free of tumor.
Pathological analysis of skin excision In most cases is routine histology is sufficient (HE staining) additional
techniques are possible if needed like molecular pathology (<5%) and
Microscopy immunohistochemistry (10-15%).
1. Determine tumor type/diagnosis: Line of differentiation, Benign Immunohistochemistry: usage of an antibody directed against an antigen on a
or malignant. (tumor) cell. The binding is subsequently visualized with a chromogen.
Molecular diagnostics: analysis of DNA alterations in the tumor. Mutations by
2. Determine tumor stage: tumor depth (<0.8mm no
NGS, translocations by RNA fusion assay and CNV by SNP array to
consequences): invasion in deeper structures, ulceration. establish/confirm diagnosis and to establish sensitivity for targeted therapy.
, 3. Assessment of margins: completely or incompletely removed.
Potential clinical consequences: Re-excision or not, Additional imaging, Excision of sentinel (draining)
lymph node, Adjuvant local radiotherapy, Adjuvant systemic therapy
Upper part of the skin is made of the epidermis and keratinocytes. When there is no atypia shown
you know it is a wart. When there is atypia and the neoplasm starts invading but still shows
keratinization it is a squamous cell carcinoma.
Skin tumors according to their origin
Wart is a benign epidermal tumor. Warts are typically small, rough, hard growths that are similar in color to the rest
of the skin. It sticks to the epidermus and shows a lot of hyper keratinization. Warts are caused by infection with a
type of human papillomavirus.
Squamous cell carcinoma is a malignant epidermis derived tumor. Typical SCC has nests of squamous epithelial cells
arising from the epidermis and extending into the dermis. Like normal cells they show desmosomes (cell structure
specialized for cell-to-cell adhesion) in between the cells but with large nuclei and varying in size and color. There is
also keratinization like normal skin. SCC occurs
especially in areas with cumulative sun-exposition, it
has a UV-specific mutation signature (CC to TT
mutations).
When the SCC is not invasive yet it is called pre-
malignant.
Basal cell carcinoma are derived from hair follicles. Key feature is arising of
basaloid cells from the epidermis, this are cells with very dark nuclei. The
basaloid epithelium forms a palisade with a cleft forming from the
adjacent tumor stroma.
Most common cancer and derived from sun exposure in western world.
Only occurs in Caucasians and grow aggressively and hardly ever
metastasize.
Sebaceous adenoma and carcinoma are derived from the sebaceous gland. It has much
more present basal layer (dark purple). A normal gland is connected to a hair follicle,
an adenoma is not. The carcinoma grows invasive and shows atypia.
A sebaceous tumors etiology can be from UV exposure or part of Muir-Torre
syndrome, this is a rare hereditary autosomal dominant cancer syndrome. The genes
affected are MLH1, SMH2 and MSH6, and are involved in DNA mismatch repair.
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation
of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Merkel cell carcinoma is derived from merkel cells in the epithelium. Merkel cells are
epithelial cells that lie solitary in epidermis. They are sensitive to light touch and in thus in
contact with the nerves. We don’t know what they look like but the carcinoma shows as
small blue round cells. In HE staining it stains dark blue because they are hyperchromatic.
This tumor often occurs in older patients who often immunosuppressed
and has a very bad prognosis. The tumor is caused by sunlight or by the
merkel cell virus.
Langerhans cells are specialized dendritic cells in the skin. In the staining you can see they
have dendritic cells. Langerhans cells act like sensors for antigens in the skin. When
inflammation happens they take up antigen and go to lymph node and activate T-cells by
showing them the antigens, the T cells than act against inflammation.
Can cause Langerhans cells histiocytosis. Only occurs in children and adolescents. There are
then way to many cells in epidermis and dermis. This tumor has a mutation in BRAF V600E.
Melanocytic tumors BRAF V600E is always a somatic mutation. This gene is part of the
A melanocyte is a melanin-producing neural crest-derived cells that migrate after 8 mapk pathway, the mutation leads to enhancement of proliferation
and survival. It is a hotspot mutation in different kind of tumors like
weeks after fertilization to the the nevi, melanoma, lung cancer and colon cancer.
bottom layer of the skin’s epidermis,
the middle layer of they eye, the
inner ear and heart. Melanin is a dark pigment primarily responsible for skin color. Once
synthesized, melanin is contained in special organelles called melanosomes which can be
transported to nearby keratinocytes to induce pigmentation. Melanin serves as protection
against UV radiation. Melanocytes also have a role in the immune system.
Benign melanocytic tumors
Benign melanocytic tumors occur due to increased proliferation (nevi) or, less frequent, due to
disturbed migration during development.
, Molecular alterations in melanocytic tumors A driver mutation is an early mutation in tumors
- Mutations and stay present in case of malignant progression.
o Driver mutations in a It is a hotspot mutation like V600E, most effective
way to cause constant activation of oncogene.
oncogene BRAF, NRAS, HRAS, KIT, GNAQ, GNA11 are
o Loss of function mutations in a oncogenes in melanocytic tumors. Different
tumor suppressor gene oncogenes are involved in different nevi.
- Structural chromosomal alteration:
translocation
- Copy number variation: loss or gain of part of a chromosome
There are different benign nevi with a different clinic, histology and genetics.
Common acquired melanocytic nevus have we all. It is develop mostly in the first 2 years
of life, most people have 20-30 common nevi. 60% BRAF V600E and 20% NRAS Q61R. A
common nevi can be junctional (melanocyte only present in epidermis), compound
(melanocyte s present in epidermis and in dermis) and dermal (cells are only present in
dermis).
In time a benign junctional nevi drops down and becomes a dermal nevi.
Congenital nevus is a nevus that is present at birth. The small ones (<1.5cm) are common. The large ones is very rare and
often accompanied by a number of satellite nevi. When there are many cell with this driver mutation and proliferate more
than normal melanocytes so there is a higher change of developing a melanoma.
It looks like a dermal nevus except the melanocytes grow very deep and surround the hair
follicle, oil gland and the sweat duct.
The small and medium sized congenital nevi often have the BRAF mutation. The large
congenital nevus often have the NRAS mutation.
Blue nevi are present in 0.5-4% of light skinned adults. It is usually solitary blue papule and
<1 cm in diameter. It can occur anywhere. Very dark melanocytes that is
always located dermally.
The cells are difficult to recognize. The dark pigments are not the melanocytic
cells but macrophages that take up the melanin (melanophages).
Blue nevus has the GNAQ or GNA mutation in a hotspot. The genes are
involved in the melanoma in the eye, perhaps these cells had a problem with
migration.
Spitz nevus is an uncommon type of nevus. Present in the face and extremities of young patients. Grows rapid in a few months and
then forms a dome shaped nodule. They are red, reddish-brown or darker.
The form dome shaped lesion, symmetrical. Are formed by large cells and look a lot like epithelial cells (epitheloids), they have a
pink cytoplasm and mitoses can be present.
Because it is a spitz nevi we accept this type of atypia, otherwise we would call it
a melanoma. Usually they don’t have mutation but a translocation in ALK, BRAF,
NTRK, ROS, MET. Most are receptor kinases are switch off but because of the
translocation or the fusion with other genes they are activated again and
activate cell survival and proliferation.
BAP1 inactivated melanocytic tumor needs three hits before it occurs.
1. Inactivation of tumor suppressor gene BAP1
2. BRAF activation mutation
3. Second loss of BAP1
Malignant melanocytic tumors: Melanoma A tumor suppressor gene lies on two loci. In order to cause
Sun is involved in the formation of melanoma. neoplasia both of these genes need to be inactivated.
Patients can have one hereditary inactivation already. Patients with
Melanoma, also known as malignant melanoma, is a type of skin cancer that germline BAP1 mutation can be screened for other types of cancer
develop from the pigment syndromes like mesothelioma, melanoma of the skin and eye.
producing cells known as
melanocytes. About 25% of melanomas
develop from moles. The main cause is
UV exposure in those with low levels of
skin pigment melanin.
Intra-epidermal melanoma is considered pre-malignant because it is not
invasive yet. The nuclei are very large (compare to nuclei
of keratinocytes. Melanocytes have nuclei that are a lot
smaller so in nevi they should not be larger than
keratinocytes). They show big variation in size, color and
morphology. early invasive melanoma has nests within the
epidermis. The small melanocytic cells are already in the
dermis. late stage melanoma has a deep invasion. Is already big part of the
skin. The melanoma is large and thick.
