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Neoplasia & - Pathology and genetic background of skin tumours

Q: 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.

30 important questions on Neoplasia & - Pathology and genetic background of skin tumours

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

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)

-> 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

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

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.

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

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 ?

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

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)

The question on the page originate from the summary of the following study material:

Human Pathology

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