Summary Class notes - Human Pathology

Course
- Human Pathology
- 2021 - 2022
- Radboud Universiteit Nijmegen
- Biologie
334 Flashcards & Notes
1 Students
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Summary - Class notes - Human Pathology

  • 1611529200 Neoplasia 1.1 & 1.2 - Pathology and genetic background of skin tumours

  • Neoplasm means
    New growth, genetically driven new growth of cells. (ook moedervlekken en wratten)

    can be: benign, pre-malignant, malignant
  • Which two type neoplasms are there?
    Benign and Malignant neoplasm
  • Characteristics of benign neoplasm
    • Only local growth
    • no invasion in other tissue
    • no metastases
    • often slowly growing
    • cell without 'atypia'
  • Characteristics of Malignant neoplasm
    • Invasion into other tissue
    • can metastasise
    • often rapid cellular growth, mitosis and meiosis
    • cell with 'atypia' 
  • Types of genetic alterations leading to neoplasia:
    • Mutations
    • structural chromosomal alterations translocations
    • copy number variations: losses or gains of parts or whole chromosomes.
    • viral transformation (not discussed in detail)
  • Mutation = a nucleotide change in DNA
    forms of mutations: 
    Substitution 

    Frameshift:
    insertion
    deletion
  • 3 types of genes can be involved in oncogenesis:
    1. (proto)oncogenes
    • funcion: promotion of cell proliferation and survival
    • mutation/amplification: gain of function/ activation/ over expression

    2. tumor suppressor genes
    • Function: inhibition of cell proliferation of induction of apoptosis
    • Mutation/loss: inactivation/loss of function
    3. mutation / mismatch repair genes

    • Function: repair of DNA replication errors
    • Mutation: loss of function (accumulation of DNA errors)
  • Two types of mutations are:
    Somatic
    • acquired
    • present only in certain cells of the body, dependent on cause
    • e.g. UV induced TP53 mutation in epithelial cells of the skin

    Germline mutations
    • Hereditary, congenital
    • present in all cells of the body
  • What are some simple alterations of Benign neoplasia's?
    • 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: clonal evolution model
    • Several mutations (usually at least 6 steps) in different genes controlling cell growth, different and death.
    • often starting with a precancerous genetic change
    • addition genetic changes lead to cancerous growth
      • autonomous cell proliferation
      • loss of cell contact inhibition: invasion occurs
      • new vessels develop
      • growth in to vessels and metastasis can occur
  • Wat is the most common type of cancer?
    Skin cancer, the incidence of skin cancer is rising very fast. (other types are decreasing)
  • What is the largest organ of the body?
    The skin. About 4 kg. That's why skin cancer rising, life long exposure to UV light.
  • Wat type of mutation is skin cancer?
    A mutation of process
  • What are mutational signatures?
    Unique combinations of mutation types generated by different mutational processes.
  • Why is skin cancer so common type of cancer?
    The skin contains a lot of different structures that can give rise to different tumors
  • Clinal examination
    Skin cut
    stained
    cut thin slices
    put on microscope slices
    stain again
  • Hisopathological investigation of (skin) tumors:
    1. Assessment of origin: from which tissue/ cells is the tumor derived?
    2. establish whether the tumor is benign or malignant (atypia, mitosis, necrosis, invasion) 
    -> Diagnosis
  • Pathological analysis of skin excision
    Microscopy
    1. determine tumor type/diagnose
    • line of differentiation
    • benign of malignant
    2. Determine tumor stage
    • tumor depth
    • invasion in deeper structure
    • ulceration (zweren)
    3. Assessment of margins: completely or incompletely removed?

    than ->


    Potential clinical consequences
    • re-excision or not
    • additional imaging
    • excision of sentinel (draining) lymph node
    • adjuvant local radiotherapy
    • adjuvent systemic therapy



    E.g.: if a melanoma deeper than 0,8 mm or shows ulceration -> excision of sentinel node -> PET-CT scan, 1 yr adjuvant (aanvullend) therapy and 5 yr clinical follow up.
  • How is a tumor diagnosed?
    • Routine histology is sufficient in most cases (HE staining)
    • additional techniques are possible if needed
      • immunohistochemistry (10-15%)
    Using antibodies directed against an antigen (of tumor cell), binding is visualised with a chromogen. 
      • molecular pathology (<5%)
    analysis of DNA alterations in the tumor
    - Mutations -> by next generation sequencing)
    - translocations -> by RNA fusion assay
    - Copy number variations -> by SNP array
    -> to establish/confirm diagnosis
    -> for establish sensitivity for targeted therapy


  • How are tumors classified?
    They are classified according to their origin.
  • What happens when one of the mismatch repair genes are lost?
    The mismatched DNA is not repaired and cancer forms.
  • What are causes (etiology) of Squamous cell carcinoma?
    1. UV exposure

    • tumors develop on sun-exposed sites
    • UV-specific mutation (CC to TT mutations)
    2. HPV = huma papilloma virus

      • especially in immune comprised patients
  • What is the precursor lesion of squamous cell carcinoma (pre-malignant) called?
    Dysplasia (= abnormal development cells)
  • Clinical features of basal cell carcinoma are:
    • Most common cancer
    • especially in areas with cumulative sun exposure 
    • frequent around eyes and nose
    • not found on mucosa, palms and soles

    • etiology: cumulative UV exposure
    • age mostly > 40
    • caucasians


    • Biological behaviour:
    • locally agressive
    • can be mutilating
    • hardly ever metastasizes
  • What are merkel cells?
    Type of epithelial cells in epidermis, sensitive to very light touch and are therefore in contact with nerves. 
    We do not really know how they look like. 
  • Define merkel cell carcinoma:
    • Probably derived from merkel cells in the epithelium
    • older patient
    • often immunosuppressed
    • very bad prognosis, rapid metastasis, progression and death
    • etiology: Merkel virus and sunlight
  • What are Langerhans cells?
    Specialized dendritic cells of the skin
  • Langerhans cell carcinoma:
    • Children and adolescents
    • large cells with dented nuclei
    • etiologie: BRAF V600E mutation
  • Melanocytes
    • 1 melanocyte communicates with 30-40 keratinocytes
    • the melanosomes protect the keratinocytes against UV damages till the DNA

    • Origin: 
      • Melanoblasts (precursors) are present in neural crest > 8 wks after fertilisation
      • melanoblasts mostly migrate to the epidermis and hair follicles
      • a few migrate to the eye/inner ear/brain

    • There are different melanocytes skin tumors
  • Development and molecular alterations in melanocytic tumor:
    - increased proliferation or/and
    - disturbed migration during development

    • mutations
      • driver mutations in a oncogene
      • loss of function mutations in a tumor suppressor gene
    • structural chromosomal alteration: translocation
    • copy number variation: loss or gain of part of a chromosome
  • Oncogenes in melanocytes tumors:
    BRAF, NRAS, HRAS, KIT, GNAQ, GNA11
    different oncogenes in different types of benign nevi
  • Drivers mutations in oncogenes:
    • Early / initiating mutations in tumors
    • stay present in case of malignant progression
    • hotspot mutations (like V600E in BRAF)
    • leading to constant activated state of the oncogene
    • constant activation of the pathway
  • What is a hotspot mutation?
    Mutation at one spot, at one gene.
    so same spot, same amino acid (number), same change
    e.g.: BRAF V600E/K
  • Different benign nevi: different clinic, histology, and genetics
    .
  • Common acquired melanocytes nevus
    • Develop mostly in the first years of life
    • most people have 20-3- common nevi


    • mutations:
      • 60% BRAF V600E/K
      • 20% NRAS Q61R/L/K
  • 3 types of acuiqered nevi
    Junctional: in epidermis
    Compound: in epidermis and dermis
    Dermal: in dermis

    it starts with junctional and in time drops down and forms compound and later dermal nevi.
  • Congenital nevus are?
    Nevus that are present at birth

    • mutations: 
      • BRAF -> in small and medium-sized congenital nevi
      • NRAS -> mutations in large congenital nevi
  • Blue nevus are?

    • present in 0.5-4% of light skinned adults
    • usually solitary blue papule
    • usually <1cm in diameter
    • can occur anywhere

    • Location: Is always in dermis, looks blue because of epidermis covering it. (on right picture are purple elongated, not the big ones)


    • Mutation: 
      • 83% GNAQ Q209L
      • &% GNA11 Q209L
  • Spitz nevus are?
    • Uncommon
    • face and extremities of children and you adults
    • rapid growth in months
    • dome shaped nodule
    • red, reddish-brown or darker papule/nodules
    • also pigmented spitz nevi


    • Mutations:
      • translocations in ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8 of RET
      • or HRAS hotspot mutation
  • BAP1 inactivated melanocytes tumor:
    BAP1 = Tumor suppressor gene

    • 3 hits need to occur to get this melanocytes tumor: 
      • Both loci need to be inactivated to get this tumor. 
      • Somatic / acquired
      • hereditair
    • BRAF activating mutation
    • Second loss of BAP1 (LOH or inactivating mutation)


    Hereditairy: germline BAP1 mutation
    - cancer syndrome
    - mesothelioma, melanoma of skin and eye
  • Development of melanoma: progression model
    Melanocyte -> nevus -> dysplastic nevus 
    -> Melanoma -> metastatic melanoma
  • With progression increase in genetic alterations
    .
  • Histology melanoma in early, early invasive and later stage/deep invasive
    .
  • Melanoma prognosis is determined by?
    • Thickness
    • Ulceration
    • Presence of nodal metastases
    • Presence of distant metastases


    TNM classification melanoma
    • T tumor/primary melanoma, T1-T4
    • N lymph node metastases, N0-N3
    • M distant metastases, M0-M1c


    Clinical stages melanoma AJCC
  • what are treatment of melanoma?
    • Primary melanoma: surgery
    • Metastatic melanoma:
      • surgery: local and mono metastases
      • systematic treatment:
      • 1. Immunotherapy: immune checkpoint inhibitors
      • 2. Targeted therapy in case BARF mutation: BRAF and MEK inhibitor.
  • Target therapy: BRAF and MEK inhibition
    • BRAF is the most frequently mutated gene in melanoma: 50-60%
    • Hotspot mutation V600E (K/R)
    • This mutation is specifically targeted
    • Addition of MEK inhibitor leads to longer survival.
  • Immunotherapy
    antigens/lichaams in this treatment drug mostly inhibits the inhibition of the T-cells, so activate them.

    Immune therapy gives higher increase of survival than targeted therapy
  • Altered proteins result in Neo-antigens
    • HLA molecules present peptides derived from degraded self proteins to T-cells
    • Mutated proteins lead to new peptides = Neo-antigens
    • comparable to foreign peptides such as infections
    • can be recognised by T-cells
    • The more DNA mutations, the more Neo-antigens
  • What is BRAF v600E/K ?
    Driver mutation in a melanoma.
  • How can detection of gene fusion (chromosomal translocation) be done?
    • Can be demonstrated by expression using IHC
    • By RNA fusion assay
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Eosin and ... Hematoxylin (HE stain) are most common used staining, what do you stain?
.... See ppt slides cytoplasm?
Slide 10, metaplasia etc..
Study very well, important for exam
Metaplasia: differentiation of cell into different type of epithelium by hormonal changes. So e.g. cylindrical epithelia (columnar cells) by hormonal changes can change/grow into squamous epithelium, or vise versa. But all these cells just have normal appearance, just function has changed.


slide
9 process is caused by metaplasia.


Infection of HPV, and messing up epithelia and abnormal differentiation results = dysplasia. So squamous epithelium grows into dysplastic epithelium.

if infection persists the malignant Neoplasia will follow the dysplasia stage.




PECs are involved in sclerosis
.
Immunological staining
.
What are three possible problems with immunological staining that one should keep in mind?
Marker specificity
  • many markers are less specific as mentioned in literature
  • specificity may change due to cell change in for instance pathological processes
Cross-reactivity between species
  • e.g. High resemblance between immunoglobulins form mouse and rat. This may and lead to cross-reactivity when using both rat and mouse antibodies.
Antibodies need different sample preparations
  • e.g. Cryo-section or paraffin section, fixative, antigen retrieval
Why do we need different antibodies of different species to stain different colors?
Because otherwise the same sheep green antibody will reactie to the same structure as the red antibody of sheep and will cooler yellow, so you won't be able to distinguish different structures anymore
Immunological staining of PECs in focal segmental glomerulosclerosis
You can stain with multiple markers
How is the role of PECs in focal segmental glomerulosclerosis studied?
With immunological stainings, why?
  • complex anatomy of the kidney
  • focal and segmental aspects of the disease
  • co-staining of multiple markers
Focal segmental glomerulosclerosis (FSGS)
The role of parietal epithelial cells (PECs)
What is the electrokinectic model?
This concepts turns the glomerular filter from a passive into an active and dynamic filter, with a self-clearing mechanism and variable size and charge selectivity. 

  • no clogging of the filter
  • it allows negative charged growth factors to travel from podocyte to endothelial cells i.e. VEGF
  • effacement of the foot processes wil disturb the flow through the filter and thus the electrokinetic effects