Diabetic Wound Healing, Inflammatory Skin Dermatoses and Cancer Dermatoses

Question 1

What are the 3 layers of the skin and the dominant cell types within them?

Answer 1

1. Epidermis:
   - Keratinocyte rich
   - Melanocytes
   - Merkel cells (nerve cells)
   - Langerhans cells (immune cells)
2. Dermis:
   - Fibroblasts (that secrete collagen)
   - Vascular network (endothelial cells)
   - Specialised structures such as hair follicles, sebacious glands and sweat glands
3. Subcutaneous Tissue:
   - Adipocytes

Question 2

What are the two types of skin?

Answer 2

1. Glaborous skin:
   - On palms of hands and soles of feet
   - Hairless skin
   - Thicker layer of keratinocytes in epidermis (for protection)
2. Hairy skin:
   - Covers rest of body
   - Contains hair follicles and associated sebacious glands

Question 3

What are the 4 basic steps of wound healing?

Answer 3

1. Homeostasis:
   - Blood clot formation (due to activation of thrombin which causes platelet aggregation)
2. Inflammation:
   - Helps prevent infection
   - Recruitment of neutrophils
   - Recruitment of macrophages
   - Macrophages signal to other cell types including keratinocytes (PDGF), fibroblasts and endothelial cells (VEGF)
   - Macrophages also debride the wound
3. Proliferation:
   - Different cell types proliferate to repopulate the wound (due to signalling from inflammatory cells)
   - Keratinocytes proliferate and migrate down edges of wound
   - Endothelial cells: proliferate to form new blood vessels
   - Fibroblasts: proliferate to deposit collagen
4. Remodelling:
   - Aims to restore tensile strength of skin to 70-80% of original
   - Collagen cross-linking and maturation
   - Elastic fiber appearance
   - Scar formation can occur

Question 4

Describe the typical process of a simple incision wound healing process:

Answer 4

1. Simple incision

Immediate:
2. Blood clot forms (homeostasis) and epithelium thickens at site of wound

24-48 hours:

3. Leukocyte infiltration (neutrophils, lymphocytes)- inflammation
4. Epithelium grows down along incision edges

5-8 days:

5. Epithelial down growth progresses (proliferative phase)
6. Fibroblast activation takes place
7. Cellular infilitration progresses (macrophages)

10-15 days:

8. Angiogenesis (endothelial cell proliferation)
9. Regression of epithelial down growth
10. Fibrosed blood clot (scab) is pushed out by proliferating keratinocytes)
11. Collagen formation progresses (remodelling)
12. Inflammation abates

3 days-9 months:

13. Epithelium is thinned to near normal
14. Tensile strength is restored to 70-80%

Question 5

What is the difference between mouse and human skin?

Answer 5

• Mouse skin has thinner epidermis and dermis

- Mouse skin is much more densely populated with keratinocytes

Question 6

What are the important stem cells involved in wound healing?

Answer 6

Niche Epidermal Stem Cells:

1. Basal Epidermal Stem Cells:
   - Found at bottom of epidermis
   - Repopulates keratinocytes
2. Hair Follicle Stem Cells:
   - Can form hair follicle and sebaceous gland
3. Intrafollicular Epidermal Stem Cell:
   - Located between epidermis and hair follicles
   - Can form many cell types
4. Adipose-derived stem cells:
   - Located in subcutaneous layer
   - Role in wound healing unclear

Circulating Stem Cells:

• In the event that a wound breaches all layers of the skin and there is a loss of local niche stem cells in that area, not only can neighbouring niche stem cells migrate- endothelial progenitor stem cells can migrate to the wound from the circulation and help form new blood vessels during the proliferative phase of wound healing

Question 7

What are the General Principles of Wound Care?

Answer 7

1. Uncover and Examine Wound:
   - Done to examine depth and also type of wound
   - Colour of wound can inform what treatment strategy will be used
2. Moisten wound:
   - Makes debridement easier
   - Cleans wound (anti-microbial cleansers used)
3. Examine Wound (if neccessary surgically debride):
   - Surgical debridement involves the removal of non-viable and dead tissue as it inhibits the wound healing process and can harbour infection
4. Treat depending on wound:
   - Topical formations on gauze e.g. antibiotics for bacterial infection, zinc cream for rash etc.
5. Carefully dress wound:
   - Hydrogel used for moist wound healing
   - Absorbant Iordosorb gel is used for dry wound healing
6. Schedule follow up appointment or specialised care

Question 8

What are the hallmarks of diabetic wounds?

Answer 8

1. Prolonged inflammation:
2. Endothelial cell dysfunction:
   - Can cause vessels to leak fluid into tissue and also comprimises angiogenesis
3. Poor keratinocyte migration
4. Poor fibroblast activation

Question 9

What is the Underlying Pathology of Diabetic Foot Ulcers?

Answer 9

1. Neuropathy:
   - Sensory neuropathy: causes decreased pain sensation, meaning patients can place excessive pressure on one part of foot without feeling pain as pathology occurs
   - Motor neuropathy: causes muscular atrophy resulting in changes to foot posture that can cause prominant bone areas to appear that are prone to ulceration
   - Autonomic neuropathy: destruction of sympathetic nerves causes constriction of peripheral blood vessels
2. Ischaemia due to peripheral vascular disease
   - Neuropathy and or ischemia is accompanied by an external trauma (e.g. pressure/sheer forces)

Question 10

How are Low Grade Diabetic Foot Ulcers Treated?

Answer 10

1. Surgical debridement
2. Topical Dressings:
   - Ischemic wounds: dressed with absorbent dressing
   - Non-ischemic wounds: dressed with hydrogel dressing
3. Pressure Reduction:
   - Pressure offloading through Styrofoam inserts or orthotics
4. Hyperbaric Oxygen Therapy

Question 11

How are Diabetic Foot Ulcers Classified?

Answer 11

Wagner Ulcer Grade Classification:
Grade 0-2: wound care nurses can manage
Grade 2-5: specialist care required (grade 4-5 usually requires amputation as gangrene has occurred)

University of Texas Classification Chart:
- Classifies wounds based on ulcer depth and comorbidities such as infection and ischemia

Question 12

What is allergic contact dermatitis?

Answer 12

• Very common rash
• Type IV delayed hypersensativity reaction (memory T-cells)
• Prototypical allergic contact dermatitis is the reaction to poison ivy (100% of population reacts)
• Many causes of allergic contact dermatitis are unknown

Question 13

What are the phases of a type IV hypersensativity response:

Answer 13

1. Sensatization Phase:

• 1st exposure to allergen
• Antigen phagocytosed by Langerhans cells and expressed on HLA
• Local T-cells reactive to that allergen proliferate and form memory T-cells

2. Elicitation Phase:
   - Re-exposure to allergen
   - the allergen is presented by Langerhans cells to memory T-lymphocyte clones
   - Immune cells migrate to the skin and cause the clinical manifestation of allergic contact dermatitis

Question 14

How is allergic contact dermatitis treated?

Answer 14

• Topical steroid on skin
• Strict avoidance of allergen
• Sedating antihistamines (to stop prurtus- itching)
• Soaks to treat dry skin
• If widespread or serious: oral corticosteroids

Question 15

How is allergic contact dermatitis treated?

Answer 15

• Topical steroid on skin
• Strict avoidance of allergen
• Sedating antihistamines (to stop prurtus- itching)
• Soaks to treat dry skin
• If widespread or serious: oral corticosteroids

Question 16

What is Bullous Pemphigoid?

Answer 16

• Large fluid-filled blisters in the sub-epidermal layer of the skin
• An autoimmune blistering condition: IgG antibodies against BP180 and/or BP230 (proteins in the hemidesmosomal plaque- between the epidermis and the dermis)
• Antibodies targeting the hemidesomes between the epidermis and dermis causes the epidermis to slough off and a blister to form

Question 17

How is Bullous Pemphigoid treated?

Answer 17

• Condition can spontaneously remit
• Topical steroids and oral steroids are used for more severe cases
• Immunosuppresants can also be used
• In rare cases IV-Ig is used (dilutes antibody pool and prevents action of patient autoantibodies)

Question 18

What is Cutaneous Lupus Erythematous?

Answer 18

• A classic red butterfly rash on cheeks
• Caused by anti-nuclear (anti-dsDNA/anti-Smith) antibodies
• Necrosis of cells causes the release of nuclear fragments which are antigen to which the antibodies react and cause inflammation

Question 19

How is Cutaneous Lupus Erythematous treated?

Answer 19

1. Sun protection and sunscreen blocking UVA (UVA exacerbates the condition)
2. Topical corticosteroids intitially, then oral steroids and then in the most serious cases cytotoxic chemotherapeutic agents such as methotrexate are used

Question 20

What is Vitiligo?

Answer 20

• Depigmentation of the skin due to loss of melanocytes/loss of their function
• Unremarkable pathology under H&E stain
• Autoimmune disease with unknown trigger and precise mechanism- often occurs in people with Type 1 diabetes and other autoimmune conditions

Question 21

How is Vitiligo treated?

Answer 21

1. Topical corticosteroids/immunomodulators
2. Very rarely- complete depigmentation
3. UV light therapy

Question 22

How is Psoriasis treated?

Answer 22

1. Topical corticosteroids
2. Vitamin A or D analogues (cytotoxic agents)
3. Cyclosporine or chemotherapeutics
4. Antibody therapies
5. UV light therapies

Question 23

What role does the skin play in vitamin D metabolism?

Answer 23

• Pro-vitamin D3 is converted to vitamin D3 in the epidermis under UVB exposure

Question 24

What is cuteneous T-cell lymphoma?

- What are the two stages of the disease?

Answer 24

• Extremely rare disease (1:500,000)
• Key feature of the disease is abnormal skin honing CD4+ T-cells with cutaneous lymphocyte-associated antigens on their surface that makes them migrate to the skin
• These pathogenic CD4+ T cells lose CD5, CD7 and CD26 surface molecules and over express CD25
• Skin of patients has high levels of CD4+ T cell infiltration
• The two stages of the diseases are:
  1. Mycosis fungoides
  2. Sezary syndrome

Question 25

What is mycosis fungoides?

Answer 25

- The early stage of cutaneous T-cell lymphoma - Has a good prognosis - Disease progression: 1. Stage 1A is asymptomatic (indolent) 2. Plaque phase (appears as non-specific dermatitis) 3. Nodules appear (formed from plaques that have progressed) 4. The disease progresses to Sezary syndrome

Question 26

What is Sezary Syndrome?

Answer 26

- The advanced malignant form of cutaneous T-cell lymphoma - Poor prognosis (no treatment shown to increase survival) - It is a erythrodermic variant of disease (involves dermis and lymphocytes) characterised by the formation of Sezary cells - Sezary cells are enlarged lymphocytes with cerebriform nuclei

Question 27

How do the different types of UV light act on the skin?

Answer 27

UVA: - Deepest penetration (into dermis) - Causes immediate tanning (due to release of melanosomes) UVB: - Intermediate penetration (mainly contained to epidermis and superior dermis) - Causes prolonged tanning due to increased melanin production UVC: - Cannot penetrate skin

Question 28

How does UV light act at a cellular level?

Answer 28

- UV light causes photo-adducts known as thymine dimers to form in the DNA of cells - Repair mechanisms in the cell (NER) can repair these dimers

Question 29

What diseases are treated with UV light therapy?

Answer 29

1. Vitiligo 2. Psoriasis 3. Cutaneous T-Cell Lymphoma

Question 30

What two types of UV light therapy are used in the treatment of targeted diseases?

Answer 30

1. UVB light: - Narrowband UVB (311-312nm) used - Affected area is exposed to narrow band UVB using lamp - More modern approach 2. UVA + Photosensitizer (Psroalen): - UVA light does not cause damage to cells at a therapeutic dose - UVA is used into combination with a chemical that sensitizes the skin to light (e.g. methoxypsoralen) - The psolarens act by binding to the minor groove of DNA, when exposed to UV light photo-adducts are formed between the DNA the the psoralen or free reactive oxygen radicals are formed to damage cell membranes

Question 31

What is Basal Cell Carcinoma?

Answer 31

- Most common (80%) and least serious form of skin cancer - Usually occur on head or next - UV light/ionising radiation and immuosuppression increases risk - Treated with micrograpic surgery or photodynamic therapy

Question 32

What is Squamous Cell Carcinoma?

Answer 32

- Second most common skin cancer (20%) - Can metastasise but this is rare as it is usually diagnosed at primary stage (lesion obvious and not aggressive) - Common on skin chronically damaged by UVB light - Managed with surgery to remove the tumour

Question 33

What is melanoma?

Answer 33

- Most aggressive form of skin cancer - Incidence relatively high and rising (1:75 people) - Caused by chronic UV exposure - Accumulation of mutations in melanocytes results in rapid proliferation of these cells - The tumour has a high propensity to metastasise (as melanocytes are derived from neural crest cells so have the ability to survive and proliferate in many sites in the body) - Local disease: treated using surgery (if caught early has excellent prognosis) - Metastatic disease: combination of surgery and chemotherapy is used by prognosis is very poor

Question 34

What is ionising radiation?

Answer 34

- Occurs when radiation causes one or more orbital electrons to be ejected from an atom - This ionisation can damage cells directly through ionising hydrogen atoms on DNA - The ionisation can damage cells indirectly by ionising water molecules causing them to form reactive oxygen species which damage critical cellular targets such as DNA

Question 35

What is radiation therapy?

Answer 35

- Uses high energy x-rays focused onto a cancer whilst minimising exposure of normal tissues (through shielding) - Given to 50% of cancer patients - Treatment aims to deliver 60 Gray units of radiation to the tumour over 6-8 weeks)

Question 36

What are the side effects of radiotherapy?

Answer 36

``` 1. Acute Injury: E.g. Dermatitis E.g. Cystitis E.g.Hair loss - Not dose limiting but can cause patients to stop adhering to therapy ``` ``` 2. Late effects: E.g. Fibrosis E.g. Atrophy E.g. Vascular Damage E.g. Hormone deficiencies - Very serious, results in hardening and wrinkling of the skin, loss of tissue function, bleeding in tissues and formation of secondary malignancies ```