Samenvatting - 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