Neoplasia & - Pathology and genetic background of skin tumours
30 important questions on Neoplasia & - Pathology and genetic background of skin tumours
Wat type of mutation is skin cancer?
What are mutational signatures?
Why is skin cancer so common type of cancer?
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Hisopathological investigation of (skin) tumors:
- Assessment of origin: from which tissue/ cells is the tumor derived?
- establish whether the tumor is benign or malignant (atypia, mitosis, necrosis, invasion)
Pathological analysis of skin excision
1. determine tumor type/diagnose
- line of differentiation
- benign of malignant
- tumor depth
- invasion in deeper structure
- ulceration (zweren)
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%)
- molecular pathology (<5%)
- 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?
What happens when one of the mismatch repair genes are lost?
What are causes (etiology) of Squamous cell carcinoma?
- tumors develop on sun-exposed sites
- UV-specific mutation (CC to TT mutations)
- especially in immune comprised patients
What is the precursor lesion of squamous cell carcinoma (pre-malignant) called?
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?
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?
Langerhans cell carcinoma:
- Children and adolescents
- large cells with dented nuclei
- etiologie: BRAF V600E mutation
Development and molecular alterations in melanocytic tumor:
- 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:
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?
so same spot, same amino acid (number), same change
e.g.: BRAF V600E/K
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
Compound: in epidermis and dermis
Dermal: in dermis
it starts with junctional and in time drops down and forms compound and later dermal nevi.
BAP1 inactivated melanocytes tumor:
- 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
-> Melanoma -> metastatic melanoma
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.
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 ?
How can detection of gene fusion (chromosomal translocation) be done?
- Can be demonstrated by expression using IHC
- By RNA fusion assay
What are some features of melanoma with a BRAFV600E mutation?
- Patients: young, lot of nevi, peak age 50 yrs, strong decline > 60 yrs
- Localisation: Skin intermittent sun-exposure (trunk, extremities)
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