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Head and Neck > Skin > Flashcards

Skin Flashcards

1
Q

What are the layers of the epidermis?

A

Stratum:
1. Corneum
2. Lucidum
3. Granulosum
4. Spinosum
5. Basale

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2
Q

List all 7 locations affected by Swanson’s H Zone

A
  1. Nose, nasal ala, septum
  2. Upper lip and Lip; junction of nasolabial fold with ala
  3. Eyelids (inner canthi and lower eyelids)
  4. Infraorbital rims and upper cheeks
  5. Lateral cheek and temple
  6. Ears - Retroauricular/Preauricular extending to temple
  7. Certain scalp regions
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3
Q

What is the significant of Swanson’s H-Zone? List 3

A

High risk cancer sites - risk of invasion, spread, recurrence
Tumors can spread along these lines.

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4
Q

List a differential for benign skin lesions that appear malignant 2

A
  • Seborrheic Keratosis
  • Chondrodermatitis Helicis (Winkler’s disease)
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5
Q

What is Chondrodermatitis Helicis? List 5 risk factors.

A

Definition: Inflammatory lesion of the skin overlying ear cartilage (typically helix in men and antihelix in females) caused by chronic trauma and pressure

Risks:
1. Chronic trauma/pressure (e.g. sleeping on one side)
2. Sun exposure
3. Cold exposure
4. Fair skin
5. Connective tissue dx (e.g. lupus, scleroderma, dermatomyositis)

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6
Q

List 3 differential of benign but possibly pre-malignant skin lesions, and their % chance of malignant transformation

A
  1. Keratoacanthoma (rare transformation)
  2. Actinic Keratosis (20% to SCC)
  3. Bowen Disease (5% to SCC)

Vancouver Pg 88

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7
Q

What is a keratoacanthoma, what is it derived from, and what is its natural course?

A

Locally destructive skin lesion derived from pilosebaceous gland (hair follicle/gland unit) that has initial rapid growth followed by spontaneous involution in 2-6 months. Natural course may also be unpredictable

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8
Q

What is actinic keratosis, what is it derived from, what does it look like, and what is its natural course?

A

Dry, erythematous, scaly skin lesion that is commonly seen in sun-damaged skin.
Can become hyperkeratotitic and form cutaneous horns

On lip = actinic chelitis

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9
Q

What is a Bowen disease, what is it derived from, what does it look like, and what is its natural course? What is a common risk factor?

A

Dervied from squamous cells, also known as intraepidermal SCC or SCC in situ.

Well circumscribed, irregular, scaly red patch.

Risk factors:
1. Arsenic
2. HPV 16
3. UV light

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10
Q

What is the Leser-Trelat sign, and what cancer is most commonly associated with this?

A

A shower of seborrheic keratoses, as a sign of internal malignancy, most commonly colonic adenocarcinoma

Vancouver page 89

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11
Q

What is the treatment of pre-malignant skin lesions?

A
  1. Curettage
  2. Cautery
  3. Excision
  4. Shave biopsy
  5. Cryotherapy
  6. Topical 5-FU
  7. TCA peel
  8. Imiquinod
  9. Intralesional interferon A
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12
Q

List 9 types of skin cancers (and break them down into 4 broad categories). What are the top two most common?

A
  1. Epidermal:
    - BCC (80-90%)
    - SCC (10-20%)
    - Merkel cell carcinoma
  2. Dermal:
    - Angiosarcoma
    - T-cell lymphoma
    - Dermatofibrosarcoma protuberans
  3. Adnexal:
    - Sebaceous cancer
    - Microcystic adnexal cancer
  4. Melanocytic:
    - Melanoma

Think about layers of skin when coming up with ddx for skin cancer!

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13
Q

List 3 types of UV light and their associated wavelengths. Which one is the most dangerous for developing skin cancer?

A

UVA (320-400nm) - low energy, tanning beds
UVB (280-320nm) - most dangerous
UVC (100-280nm) - High energy

Vancouver notes says 290 for UVB/C cutoff

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14
Q

What is the energy level of UVA and what is its impact on skin cancer?

A

Low energy (too low to alter DNA)

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15
Q

What is the energy level of UVB and what is its impact on skin cancer?

A

Medium energy, passes through atmosphere creates photochemical reaction to break DNA cross-linkages to cause DNA mutations. Also alters p53 suppressor genes.

Greatest risk to DNA and development of skin cancer

B = Bad

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16
Q

What is the energy level of UVC and what is its impact on skin cancer?

A

High energy block by ozone and does not enter atmosphere

C = Can’t Come in!

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17
Q

Describe the Fitzpatrick Skin Types (skin color, hair color, eye color, and burning ability).

Which types are high, medium, and low risk?

A

High risk - 1, 2
Medium risk - 3
Low risk - 4-6

Type 1: Very fair skin, light hair, blue/green eyes, always burns never tans
Type 2: Fair skin, light hair, blue eyes, mostly burns rarely tans
Type 3: Light skin, brown hair, brown eyes, sometimes burns gradually tans
Type 4: Olive skin, dark hair, dark eyes, rarely burns easily tans
Type 5: Brown skin, almost never burns easily tans
Type 6: Black skin, never burns easily tans

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18
Q

What are 8 types of skin cancer, in descending frequency?

A
  1. Basal cell cancer (90%)
  2. Squamous cell cancer (10%)
  3. Melanomas (2%)
  4. Cutaneous lymphoma
  5. Kaposi sarcoma
  6. Adnexal carcinoma
  7. Merkel cell cancer
  8. Dermatofibrosarcoma protuberans
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19
Q

List 24 risk factors for BCC and cutaneous SCC

A

HOST:
1. History of previous sun burns (Especially at young age)
2. Fitzpatrick type 1-2
3. Poor sun protection measures
4. Immunosuppression
5. Presence of Actinic Keratosis
6. Celtic ancestry

HEREDITARY/GENETIC:
1. Albinism (autosomal recessive)
2. Xeroderma pigmentosum (Autosomal recessive) - for BCC, SCC, melanoma - defect where nucleotide excision repair (NER) enzymes are mutated leading to deficient repair of DNA damaged by UV radiation - Japanese RR 1000x higher
3. Gorlin syndrome / Nevoid basal cell nevus syndrome (Autosomal dominant)
4. Familial atypical multiple mole melanoma (FAMMM) - CDKN2A
5. BK Mole syndrome
6. Atypical mole syndrome
7. p16 mutations
8. Oculocutaneous Albinism - increased risk of SCC and Melanoma
9. Epidermolysis Bullosa - increased risk of SCC
10. Fanconi anemia - increased risk of SCC

ENVIRONMENTAL:
1. Sun exposure (UVB worst)
2. Arsenic exposure (BCC, melanoma), soot, coal tar, paraffin oil, petroleum oil, asphalt
3. Occupation (outdoor work) - ranchers, farmers, sailors, fishermen
4. Tanning beds
5. Photosensitizing medications (e.g. Retinoids)
6. ?HPV (Verrucous SCC?)
7. History of radiotherapy / radiodermatitis
8. Burns/ulcers/scars (trauma) - Marjolin’s ulcers

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20
Q

What is the most common skin cancer?
What does it arise from?

A

Basal cell carcinoma (BCC): Epithelial malignancy arising from basal layer of epithelium

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21
Q

What are the clinical subtypes of basal cell carcinoma?
Which are high risk/low risk?
Which are the most common?

A

LOW RISK:
1. Nodular (most common)
2. Superficial
3. Keratotic
4. Adenoid
5. Infundibulocystic
6. Fibroepithelial

HIGH RISK:
1. Morpheaform/sclerosing (worst)
2. Infiltrative
3. Basosquamous (aggressive)
4. Micronodular
5. BCC with carcinosarcomatous differentation
6. Pigmented (r/o melanoma)

Nodular, superficial, and infiltrative have a combined >80% total BCCs

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22
Q

Describe the characteristics of the following BCC clinical subtypes:
1. Nodular
2. Morpheaform/Sclerosing
3. Superficial multifocal
4. Pigmented
5. Fibroepithelioma

A
  1. NODULAR (Most common)
    - Smooth, pearly round mass (nodule) with rolled edges, telangiectasias, central necrosis possible
  2. MORPHEAFORM/SCLEROSING (worst)
    - Morpheaform: Infiltrative, tip of iceberg, insidious, scar-like plaque with telangiectasias and indistinct margins
    - Sclerosing: Atrophic plaque with telangiectasia + ulceration, @ H-zone
  3. SUPERFICIAL MULTIFOCAL
    - Scaly erythematous patch, indistinct borders, subtle pearly border
    - Typically found on trunk, common for arsenc/rads exposure
  4. PIGMENTED
    - Contains benign melanocytes
    - Black
    - Can resemble melanoma
  5. FIBROEPITHELIOMA
    - Pedunculated
    - Usually on back
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23
Q

What are the histologic subtypes of cutaneous BCC? 4

A
  1. Solid
  2. Adenoid (tubular glands)
  3. Cystic
  4. Keratotic (aka. Basosquamous) - means towards the hair
    SACK

Hussain’s lecture:
1. Undifferentiated:
- Pigmented
- Superficial
- Sclerosing
- Infiltrative

  1. Differentiated:
    - Keratotic
    - BCC with sebaceous differentiation
    - Adenoid BCC (tubular)
    - Noduloulcerative
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24
Q

Describe the Histology of cutaneous BCC. List 6 features

A
  1. Rests of small blue cells arising from the BASAL layer (basement membrane). Cell typically large, oval or elongated nucleus, little cytoplasm.
  2. High nuclear:cytoplasmic ratio
  3. Peripheral palisading of nuclei - parallel arrangement of tumor nuclei (like a picket fence)
  4. Mucinous connective tissue stroma organized around parallel bundles around tumor masses (causes peripheral palisading of nuclei and stromal retraction - “peritumoral lacunae”)
  5. Clefting (artifact: dehydration of stroma during slide fixation causes detachment of tumor islands - empty spaces around tumor nests)
  6. Keratin pearls adjacent to tumor (not within tumor like SCC)
  7. Low magnification - basement membrane looks like its extending and making massive tumors

Vancouver 87

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25
Q

Describe the clinical presentation of cutaneous basal cell carcinoma 7

A
  • Slow growing but can be locally destructive
  • Nodular and pearly
  • Prominent telangiectasia
  • Raised borders
  • Centrally ulcerative
  • Pruritic
  • RARELY metastasizes (< 0.5%) - relies on dermal stroma underneath for its growth
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26
Q

Regarding Gorlin Syndrome, discuss:
1. What is it? Other names?
2. Genetics and Inheritance?
3. Clinical presentation?
4. What is the diagnostic criteria?

A

GORLIN SYNDROME:
- = Nevoid Basal Cell Carcinoma Syndrome

INHERITANCE/GENETICS:
- Autosomal Dominant
- PTHC gene on Chromosome 9q

CLINICAL PRESENTATION:
- Multiple (hundreds) of small cutaneous nodules appear in childhood
- As child ages, multiple basal cell carcinomas develop and lesions become aggressive - invasion, destruction, mutilation
- Rib and Vertebral abnormalities
- Frontal bossing
- Falx cerebri calcification
- Mental retardation
- Cataracts
- Odontogenic keratocysts (OKC) - 75%
- Scoliosis
- Bifid ribs
- Pitting of the palms and soles

DIAGNOSTIC CRITERIA: 2 Major OR 1 major + 2 minor

MAJOR CRITERIA:
1. ≥2 BCCs or 1 BCC in a person younger than 20 years
2. Odontogenic keratocysts of the jaw
3. 3 or more palmar or plantar pits
4. Ectopic calcification or early (< 20 years) calcification of the falx cerebri
5. Bifid, fused, or splayed ribs
6. First-degree relative with NBCCS

MINOR CRITERIA:
1. Macrocephaly
2. Congenital malformations - cleft lip or palate, frontal bossing, eye anomaly (cataract, coloboma, micro-ophthalmia, nystagmus)
3. Other skeletal abnormalities - Sprengel deformity (shoulder blade too high on one side), pectus deformity, polydactyly, syndactyly, or hypertelorism
4. Radiologic abnormalities - bridging of the sella turcica, vertebral anomalies, modeling defects or flame-shaped lucencies of hands and feet
5. Ovarian and cardio fibroma or medulloblastoma (the latter is generally found in children ≤2 years old)

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27
Q

Regarding Xeroderma Pigmentosa, discuss:
1. What is it?
2. What is the genetics and inheritance?
3. What are the risk factors?
4. What are the clinical features? Name 5-7
5. What is the prognosis like? What do they usually die from?

A

XERODERMA PIGMENTOSA (XP):
- Genetic defect that impairs ability to repair skin damage by UV light (causes extreme UV light sensitivity of the skin and eyes)

GENETICS/INHERITANCE:
- Autosomal Recessive cr 9
- Multiple genes, including:
- XPA/B/C/D
- ERCC2 & 3
- POLH

RISK FACTORS:
1. 6x more common in Japanese

CLINICAL FEATURES:
- Dry skin
- Irregular freckles
- Severe burns from being in sun for a few minutes
- Eye/eyelid problems
- Progressive neurologic abnormalities
- Multiple BCCs (most common), but also high risk for SCC and melanoma
- First skin cancer usually < 10 yo (especially without skin protection)

PROGNOSIS:
- Early death most often secondary to metastatic SCC/melanoma

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28
Q

What are the risk factors for recurrence of BCC? Please stratify into Low risk factors and High risk factors

A

SIRS PRay for LeBanese
Size
Immunosuppression
Radiation exposed-site
Subtype (aggressive vs. non-aggressive forms)
Perineural invasion
Recurrent vs primary BCC
Location
Borders

LOW RISK:
1. Trunk, extremities < 2cm
2. Well-defined borders
3. Primary BCC
4. No immunosuppression
5. No radiation exposure to site
6. Nodular and superficial subtypes
7. No perineural involvement

HIGH RISK:
1. Trunk and extremities ≥ 2cm
2. Cheeks, forehead, scalp, neck, and pretibial any size
3. Head, neck, heads, feet, pretibia, and anogenital (any size)
4. Poorly defined borders
5. Recurrent BCC
6. Immunosuppression history
7. Site of previous radiation
8. Aggressive growth patterns/subtypes
9. Perineural involvement

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29
Q

What are the high risk clinical features of BCC?

A
  1. OVERALL HIGH RISK CLINICAL FEATURES:

A. Local clinical features
- Primary site ear or non-hair-bearing lip (vermillion of the lip)
- Size with site including the erythema part
- M Area: Cheek, Forehead, Scalp, Neck > 10mm
- H Area (face) > 6mm
- Ill-defined borders
- Recurrent
- Extensive disease
- Arising from pre-existing scar, burn (Marjolin’s ulcer)

B. Symptoms
- Rapidly growing (>4mm/month)
- Neurological symptoms (suggest PNI)

C. Systemic:
- Immunosuppression (transplant, HIV, CLL, Drugs)
- Chronic inflammatory disease
- Xeroderma Pigmentosa
- Previous Radiation

D. Palpable Regional disease

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30
Q

What are the high risk pathological features of BCC?

A

A. Tumor > 2cm

B. Poor differentiation or undifferentiated

C. High risk subtypes:
- Adenoid or Acantholytic, Adenosquamous, Metaplastic (carcinosarcomatous), Basosquamous
- Spindle cell associated with high risk PNI but itself is not listed as high risk
- Presence of Desmoplasia (growth of fibrous connective tissue)

D. Depth:
- > Clark IV
- > 2mm depth (vertical distance from top to the bottom of the tumor);; Meta-analyses show 4mm and 6mm cutoffs as prognosis for recurrence and metastasis;; NCCN chose thickness >6mm or invasion beyond subcutaneous fat to be considered high risk (Scottish Guidelines - 6mm very high risk, 4mm high risk)

E. Perineural invasion, lymphovascular invasion

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31
Q

What are the SCC clinical subtypes? Which ones are the worst prognosis?

A
  1. Acantholytic/adenoid (worse)
  2. Spindle cell (worse)
  3. Conventional
  4. Clear cell
  5. Desmoplastic
  6. Lymphoepitheliomatous
  7. Verrucous
  8. Keratoacanthoma (KA) - low grade squamous neoplasm
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32
Q

Describe the 5 main histological subtypes of squamous cell carcinoma?

A
  1. Spindle cell – pleomorphic, anaplastic, little/no keratinization, lymphoepithelioma-like carcinoma
  2. Adenoid – Adenosquamous, pseudo-glandular arrangement, similar to mucoepidermoid, mucinous
  3. Generic – well-differentiated, actinic changes
  4. Bowenoid – from Bowen’s disease
  5. Verrucous – white cauliflower like lesion, HPV associated

Very SAGgy Boobs are anNOIying

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33
Q

What are the low risk factors and stratification for cutaneous SCC for local recurrence, metastasis, or death from disease?

A

Note: General characteristics (clinical and histologic) are similar to the ones in the BCC risk of recurrence flash card

Thinks: SIRS PRay for LeBanese
Size
Immunosuppression
Radiation exposure
Subtype / scar
Perineural/lymphovascular invasion
Recurrent vs. primary
Location
Borders

LOW RISK:
- Trunk, extremities ≤ 2cm
- Well defined borders
- Primary SCC
- No immunosuppression
- Not at site of previous radiation
- No neurologic symptoms
- No rapid growth
- Well or moderately differentiated
- None of the following histologic features: Acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) subtypes
- Dpeth (thickness/level of invasion): ≤6mm and no invasion beyond subcutaneous fat
- No perineural involvement
- No lymphatic or vascular involvement

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34
Q

What are the high risk factors for cutaneous SCC. 8

A

Thinks SIRS PRay for LeBanese
Size/depth
Immunosuppression
Radiation site history / scar history/background of inflammation
Subtype
Perineural/lymphovascular invasion
Recurrent vs primary SCC
Location
Borders

HIGH RISK:
- Trunk, extremities > 2cm, ≤ 4cm
- Head, neck, hands, feet, pretibia, and anogenital (any size)
- Poorly defined borders
- Recurrent tumor
- History of immunosuppression
- Site of prior RT or chronic inflammatory process
- Rapidly growing tumor
- Neurologic symptoms
- Presence of one of the histologic features: Acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) subtypes
- Positive perineural involvement
- No lymphatic or vascular involvement

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35
Q

What are the very high risk factors for cutaneous SCC

A

Think T3/4 criteria, plus poor differentiation and desmoplastic SCC

VERY HIGH RISK:
- > 4cm in any location
- Poor differentiation
- Desmoplastic SCC
- >6mm or invasion beyond subcutaneous fat
- Tumor within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1mm
- Positive lymphatic or vascular involvement

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36
Q

What are the 3 BCC and 2 SCC with worse prognosis (cutaneous)?

A

BCC
1. Sclerosing/morpheaform BCC (clinical)
2. Keratotic BCC (histologic)
3. Recurrent

SCC:
1. Spindle cell
2. De novo SCC (not pathological - non-skin damaged skin)
3. Adenoid / Acantholytic also bad

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37
Q

What are the general indications for imaging in cutaneous SCC/BCC? List 4

What are the different modalities that can be used?

A
  1. Extensive disease (deeper than what you think)
  2. Palpable positive regional disease (CT of nodal basin, plus CT A/P or FDG-PET/CT)
  3. Imaging to determine the extent of a primary tumour (Scottish guideline) - e.g. Symptoms suggestive of perineural invasion (e.g. numbness), or Clinical evidence of bony erosion
  4. High risk sites (e.g. on or around the ear)

Modalities
1. U/S ± FNA
2. CT
3. MRI
4. PET scan

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38
Q

Overall, what are the management options for cutaneous malignancies? List all the possible options

A
  1. Observation
  2. Medical (e.g. topical 5-FU, imiquimod, retinoic acid, interferon-a)
  3. Surgical: electrodessication & curettage, excision, cryosurgery, photodynamic therapy, mohs surgery
  4. Radiotherapy: Generally not indicated due to duration, complications, carcinogenesis, lack of margin control, and increased aggressiveness of recurrences
  5. Systemic therapy/chemotherapy
  6. Elective neck dissection in cSCC (not BCC): controversial but may be considered in T3/4 and high risk lesions
    - Posterior scalp and upper neck: posterolateral SND (II-V + postauricular + suboccipital LN)
    - Preauricular, anterior scalp, and temporal region: parotidectomy and facial, II, III, Va
    - Anterior and lateral face: SND partoidectomy and facial, level I-III
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39
Q

Regarding Curettage and Electrodessication (C+E), discuss:
1. What are the indications? 3
2. What are the contraindications? 2
3. What are the disadvantages?

A

INDICATIONS:
- Local Low-risk cSCCs, Superficial lesions (Biopsies must be taken to ensure no high-risk pathologic features require additional therapy)
- Pre-malignant (Carcinoma in situ)
- Alternative primary treatment for local high/very-high risk tutors in the M area (cheek, forehead, scalp, neck, pre-tibial) that are < 6mm in depth and confined to the dermis) for patients with ++comorbidities or factors making surgical excision difficult

CONTRAINDICATIONS:
- Areas with terminal hair growth (scalp, pubic or axillary regions, beard area in males) - risk of tumor extending down follicular structures and not adequately removed
- Subcutaneous layer reached - surgical excision should be performed instead (hard to distinguish tumor in sub-cut area)

DISADVANTAGES:
- No histologic margin assessment

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40
Q

Regarding wide local excision of cutaneous BCC/SCC, what are the margins?

A

Margins: must include any peripheral rim of erythema counted as tumor

  1. Local low-risk cSCC, well-circumscribed
    - < 2cm diameter: 4mm margins (clear margin 95%)
    - >2cm diameter: 6mm margins (clear margin 95%)
  2. Local high/very-high risk cSCC
    - High-risk locations (scalp, ears, eyelids, nose, lips) or other high-risk features (Grade ≥ 2, invasion of subcutaneous tissue)
    a. Diameter < 1cm - 4mm margin
    b. 1-1.9cm - 6mm margin
    c. ≥2cm - 9mm margin
    - European Guidelines: 6-10mm peripheral clinical margins for high/very high risk cSCC - greater if indicated, if clinically feasible
  • Margins generally based on location (hard to go all the way)
  • In general, BCC/SCC low risk 3-4mm sufficient; high risk 5-10mm dependent on location
  • Re-excision with post-operative margin assessment recommended after all excisions (Tissue rearrangement/flaps should not be undertaken until clear margins identified;; Close multiple disease - avoid local flap)
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41
Q

Regarding Mohs Micrographic surgery for cutaneous BCC/SCC, discuss:
1. What are the preferences/indications?
2. What are the contraindications?
3. What are the risk factors for metastasis after Mohs surgery?

A

INDICATIONS:
- Treatment option for all types of lesions because of intra-operative analysis of 100% of excision margin
- Preferred for local, very high risk cSCC

CONTRAINDICATIONS:
- Non-melanoma skin cancer that extends into the subcutaneous tissue

RISK FACTORS FOR METS POST MOHS:
- Size >2cm
- Clark level III-V
- Poor differentiation
- Areas of prior radiation
- Small tumor nests and infiltrative tumor strands
- Single cell infiltration
- PNI
- Acantholysis

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42
Q

What are the primary treatment options for low risk BCC?

What happens if there are positive margins under standard excision measures?

A
  1. Curettage & electrodessication (C+E)
  2. Shave removal (shoudl not be considered if tumor extends beyond dermis)
  3. Standard excision with 4mm margin assessment
  4. Radiation therapy (non-surgical candidates)
  5. Non-surgical modalities for superficial tumors without dermal extension
    - Topical imiquimod (preferred)
    - Topical 5-fluorouracil
    - Photodynamic therapy (e.g. topical aminolevulinic acid, porfimer sodium)
    - Cryotherapy

Positive margins after excision options:
1. Mohs
2. Re-excision
3. Radiotherapy

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43
Q

What are the primary treatment options for high risk BCC?

What happens if there are positive margins under standard excision measures?

What happens if there is negative margins?

A
  1. Mohs
  2. Standard excision with margins
  3. Radiotherapy

Positive margins options:
1. Re-resect if possible
2. Radiotherapy
3. Systemic therapy

Negative margins options:
1. Consider adjuvant RT if extensive perineural or large-nerve involvement

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44
Q

What are the treatment options for advanced cutaneous BCC?

A

LOCALLY ADVANCED BCC:
1. Surgery ± neoadjuvant systemic therapy
2. Mohs
3. Radiotherapy
4. Systemic therapy

NODAL DISEASE:
1. Surgery
2. Systemic therapy
3. Clinical trial

DISTANT METASTASES:
1. Systemic therapy
2. Radiotherapy
3. Surgery for limited metastatic disease
4. Palliative and best supportive care

Can say clinical trial for anything advanced - wouldn’t be wrong

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45
Q

What are the general indications for radiotherapy for cutaneous BCC? 3

A
  1. Low risk BCC after positive margins with standard excision.
  2. High-risk BCC as additional treatment after standard excision, Mohs, or other forms of PDEMA with positive margins
  3. Adjuvant treatment after negative margins in case of extensive perineural or large-nerve involvement.
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46
Q

What are the general indications for radiotherapy for all skin tumors? 7

What are the contraindications? 3

A

INDICATIONS:
1. Massive tumors (SCC >2 cm)
2. Very aggressive (Merkel cell)
3. Invasive (bone, muscle, cartilage, and nerve)
4. Resection margins uncertain or positive
5. Multiple recurrences
6. Marjolin’s ulcer (ie. Cancer arising from scar)
7. To the neck – Multiple positive nodes, extracapsular spread and lymphovascular invasion

CONTRAINDICATIONS:
1. BCC arising from underlying syndrome (e.g. Xeroderma pigmentosum, Gorlin, SLE)
2. Scleroderma
3. Relatively in verrucous carcinoma (radioresistant)

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47
Q

What are the indications for superficial therapies for skin cancer? 3

A
  1. Superficial BCC (not invading into dermis)
  2. Surgery or Radiotherapy is contraindicated or impractical
  3. Pre-malignant lesions
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48
Q

Regarding topical therapies for skin cancer, discuss:
1. What are the options, their MOA, and treatment regimens?

A
  1. IMIQUIMOD 5%
    - Immune response modular - Toll-like receptor 7 agonist (TLR7)
    - Indications: Nodular and superficial BCC, premalignant lesions
    - Dosage for AK: 5% 2 times per week prior to bedside for 8 hours, remove with soap and water, x 16 weeks
    - Dosage for BCC: Apply once daily prior to bedside, 5 days/week for 6 weeks
  2. 5-FLUOROURACIL (5-FU)
    - 1% cream for pre-cancerrous
    - BID application x 3-6 weeks
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49
Q

Regarding systemic therapies for BCC, discuss:
1. What are the indications?
2. What are the therapy options and mechanism of action?
3. What are some of their side effects?
4. What are the limitations to these systemic therapies?

A

INDICATIONS:
1. Locally advanced BCC (Vismodegib, Cemiplimab, Sonidegib)
2. Metastatic BCC (Vismodegib, Cemiplimab)
3. Nodal BCC (Vismodegib, Cemiplimab, Sonidegib)
4. Recurrence following surgery
5. Unresectable or not candidates for Surgery/RT

HEDGEHOG SIGNALING PATHWAY INHIBITORS (HHI):
1. Vismodegib (locally advanced or metastatic, recurrence)
- Also reduced incidence in BCC lesions in Nevoid BCC syndrome
- Side effects: Muscle spasm, alopecia, taste loss, weight loss, decreased appetite, fatigue, nausea, diarrhea

  1. Sonidegib (locally advanced, recurrence) – similar side effects as Vismodegib

Limitation to HHI: Advanced BCC can develop resistance

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50
Q

Regarding Immunotherapy for skin cancer, discuss:
1. What are the options? Which one is currently approved?
2. What are the indications? 4

A

PD-1 inhibitors (checkpoint inhibitors)/anti-PD-1 immunotherapy:
- Cemiplimab (only one approved)
- Nivolumab
- Pembrolizumab

Indications:
1. Locally advanced BCC (including neoadjuvant)
2. Metastatic BCC
3. Previously treated with HHI
4. HHI not appropriate

51
Q

What is the utility of chemotherapy in cutaneous BCC?

A

Limited due to rarity of advanced BCC in general (limited to case reports)

52
Q

List the indications for Moh’s surgery in BCC (11)

A
  1. Aggressive histology or growth pattern - morpheaform or keratotic for BCC; infiltrative type; sclerosing and keratinizing (basosquamous or metatypical); poorly differentiated SCC; de novo lesion
  2. Incompletely excised tumor
  3. Tumors with poorly defined margins
  4. Immunosuppressed patients
  5. High risk location (H-zone)
  6. Skin cancer in irradiated skin
  7. Recurrent tumor or positive margins
  8. Tumors with neurotropism
  9. Size > 0.6cm in high risk area, or > 1cm on scalp, face, neck
  10. Young patients, cosmetically important area
  11. Tumors involving vital structures

Again, think about SIRS PRay for LeBanese risk factors! Matches all of them!

53
Q

What are the tumor types that are treatable with Moh’s surgery? (14)

A
  1. BCC
  2. Cutaneous SCC
  3. Selected mucosal SCC
  4. Bowen’s disease
  5. Keratoacanthoma
  6. Verrucous carcinoma
  7. Microcystic or other adnexal neoplasms
  8. Dermatofibrosarcoma protuberans
  9. Malignant fibrous histiocytoma
  10. Atypical fibroxanthoma
  11. Extramammary Paget’s disease
  12. Merkel cell carcinoma
  13. Cutaneous rhabdomyosarcoma
  14. Lentigo Maligna

Vancouver Pg 90

54
Q

Regarding Photodynamic therapy, discuss:
1. What are the options?
2. How do they work?
3. What is the efficacy?
4. What are the side effects?

A

OPTIONS:
1. Porphyrin
2. 5-ALA (5-Aminolevulinic acid)

MECHANISM OF ACTION:
- Give a photosensitizing medication topically
- Activated by light (laser) –> causes necrosis

EFFICACY:
- Low ~ 45%
- Can treat many lesions simultaneously or used in palliative cases

SIDE EFFECTS:
- Edema
- Erythema
- Ulceration/blistering

55
Q

Regarding Dermatofibrosarcoma Protuberans, discuss:
1. What is it?
2. What is the genetics?
4. What is the typical histological stain?
5. How does it usually present? What is the rate of metastasis?
3. What are the risk factors? 5
4. What is the treatment? 4

A

DERMATOFIBROSARCOMA PROTUBERANS:
- Rare aggressive soft tissue sarcoma

Genetics:
- t(17;22) translocation (chromosome translocation from 17 to 22)
- Results in fusion of PDGFB to COLIA1 gene

Histology:
- CD34 staining

CLINICAL PRESENTATION:
- Most commonly found on torso, but can also be seen on the arms, legs, and H/N
- Tendency to recur
- Behaves like a “benign” tumor in many areas, but in 2-5% can metastasize
- 1-5% risk of metastasis. high rate of local recurrence

RISK FACTORS:
- Associated with re-arrangement of genetic material between chromosome 17 + 22
- Scar that develops after a burn or surgery/keloids may increase risk for DFSP
- Women
- Adults 3-5yo
- African americans

TREATMENT:
1. Surgical excision with 2-4cm margins and reconstruction (OR preferable)
2. Moh’s surgery
3. Adjuvant radiotherapy in high risk patients (e.g. positive or close margins)
4. Imatinib: BCR-ABL/cKIT TKI has been approved for treatment in patients with recurrent, unresectable or metastatic tumors

56
Q

Regarding low risk cutaneous SCC, what are the primary treatment options? What are the secondary treatment options if surgical options are positive?

A
  1. C&E
  2. Shave removal (unless tumor obviously extends beyond dermis)
  3. Standard excision with margins
  4. Mohs
  5. Radiotherapy

Positive margins:
1. Mohs
2. Re-excision
3. Radiotherapy

57
Q

Regarding high or very-high risk cutaneous SCC, what are the primary treatment options? What are the secondary treatment options if surgical options are positive? What if margins are negative?

A
  1. Consider SLNB in recurrent or multiple high-risk features cases
  2. Mohs
  3. Standard excision
  4. Radiotherapy
  5. Systemic therapy

Positive margins:
1. Re-resect
2. Radiotherapy
3. Systemic therapy

Negative margins:
1. Consider adjuvant radiotherapy

58
Q

Regarding very-high risk cutaneous SCC with significant local recurrence risk of nodal metastases, what are the primary treatment options?

What are some additional considerations to have for primary treatment?

What are the secondary treatment options if surgical options are positive?

What if margins are negative?

A
  1. Consider SLNB
  2. Consider neoadjuvant cemiplimab if:
    - Very rapid growth
    - In-transit metastasis
    - Lymphovascular invasion
    - Borderline resectable
    - Surgery that may not be curative or significant functional limitation

PRIMARY TREATMENT:
1. Mohs
2. Standard excision
3. Definitive Radiotherapy

Positive Margins:
1. Re-resect
2. Radiotherapy
3. Systemic therapy

Negative Margins:
1. Consider adjuvant radiation

59
Q

Regarding locally advanced or unresectable cutaneous SCC, what are the primary treatment options? 5

A
  1. Neoadjuvant therapy with Cemiplimab, plus:
  2. Mohs
  3. Standard excision with wider margins (if positive or negative margins, same treatment as previous card)
  4. Radiotherapy ±
  5. Systemic therapy
60
Q

What is the most common location for nodal metastasis or cutaneous SCC?

A

Parotid

61
Q

What are risk factors for regional nodal disease in cutaneous non-melanoma malignancies? 10

A

PATIENT FACTORS:
1. Male
2. Immunosuppression
3. Delayed presentation

TUMOR FACTORS:
1. Tumor size 2cm (13 vs. 68%)
2. Depth 4mm, thickness 6mm
3. Clark level IV
4. Invasion of adjacent tissue
5. Location
6. Presence of perineural and lymphovascular invasion
7. Tumor grade (17% vs 4%)
8. Growth Rate

INITIAL TREATMENT FACTORS:
1. Inadequate primary treatment including incomplete resection
2. Failure to consider re-excision or adjuvant EBRT with subsequent persistent disease

RECURRENCE FACTORS:
1. Site: Local recurrent specifically lip and ear (35 and 45% risk)

Study of D’Souza and Clark: High Risk Factors for LN Metastases
1. Size > 2cm: 20-30%
2. Invasion into subcutaneous fat (Depth >5mm): 16-45%
3. Poorly differentiated/ metatypical/ morpheophorm phenotype: 12-32%
4. High grade or desmoplasia: 12%
5. Perineural invasion: 40-47%
6. Lymphovascular invasion: 40%
7. Location near parotid (ear, temple, forehead, anterior scalp) or lip: 10-30%
8. Local recurrence: 25-62%
9. SCC in pre-existing scar (burn or trauma): 38%
10. Immunosuppression: 13-20%

62
Q

What are the most common primary sites that lead to parotid metastasis? 3

A
  1. Cheek
  2. Pinna
  3. Temple Forehead
63
Q

What is the O’Brien Clinical Staging of Parotid involvement of nodal metastasis?

A

PAROTID
1. P0: No clinical disease in the parotid
2. P1: Metastatic node up to 3cm in diameter
3. P2: Metastatic node >3cm and up to 6cm in diameter, or multiple nodes
4. P3: Metastatic node >6cm in diameter or disease involving 7th nerve or skull base

NECK
1. N0: No clinical disease
2. N1: Single ipsilateral neck node up to 3cm in diameter
3. N2: Single node >3cm in diameter or multiple nodes or contralateral nodes

64
Q

When should a superficial vs. total parotidectomy be performed for parotid metastasis? 1

A

Superficial parotidectomy is sufficient if no facial nerve involvement (deep parotid often not involved; however often will get irradiated after superficial parotidectomy)

65
Q

Summarize the treatment of nodal disease with parotid involvement and/or neck involvement in cutaneous non-melanoma malignancies.

A

Vertical line drawn through EAC
- Anterior - parotid is the first Echelon ± EJ
- Posterior - level V first Echelon ± EJ

P0 N+
- Elective Parotidectomy is not generally advocated for patients with isolated neck disease
- General guideline: Comprehensive neck dissection + adjuvant radiotherapy (radiation includes the parotid gland in patients where the parotid intervenes between the primary and known nodal disease
- Anterior lesion P0N+ = consider parotidectomy
- Posterior lesion P0N+ = may not necessarily include the parotid

P+ N0 & Anterior or external ear
- Parotidectomy + SND I-III
- Adjuvant rads if neck negative = parotid
- Adjuvant rads if neck positive = parotid & neck

P+ N0 & Posterior, scalp, or neck
- Parotidectomy + SND (II-V)
- Adjuvant rads if nodes negative = parotid
- Adjuvant rads if neck positive = parotid + neck

P+ N0 & NOS
- Parotidectomy & comprehensive neck dissection
- Adjuvant rads neck negative = parotid
- Adjuvant rads neck positive = parotid + neck

P+ N+ & Any primary site
- Parotidectomy & comprehensive neck dissection
- Adjuvant rads: Parotid and neck

SCC Notability lecture/Nadia ppt

66
Q

Summarize the management of the N0 neck in cutaneous non-melanoma malignancy

A

Controversial

Treatment Options:
1. Observation
2. Elective Neck Dissection
3. SLNB (some European sites do this)

High Risk Primary with N0 Disease: Elective Neck Dissection options:
1. Face, scalp, anterior to half of EAC: Superficial Parotidectomy, Level II-IV neck dissection
2. Posterior to half of EAC: Level II-V neck dissection, sub-occipital and post-auricular LN
3. Lips, mid-face: Level I-III neck dissection, Consider bilateral in midline lesions

67
Q

What are the indications to radiotherapy for the neck in cutaneous non-melanoma malignancy?

A
  1. Primary for poor surgical candidates

ADJUVANT:
1. Primary lesion
- Lesions with positive margins
- Extensive PNI or large-nerve involvement

  1. Regional Disease
    - Optional if < 3cm with no ECE/ENE
    - >3cm nodes
    - Multiple LN
    - ENE +

Adjuvant radiotherapy has been the only factor that improved local control in metastatic cutaneous SCC in retrospective studies

68
Q

Regarding systemic therapy, discuss the indications in cutaneous SCC

A
  1. Very High-Risk Disease: Consider Neoadjuvant Cemiplimab-rwlc indications:
    - Very rapid growth (>4mm/month)
    - In-transit metastasis
    - Lymphovascular invasion
    - Borderline resectable
    - Surgery alone may not be curative
  2. Primary & Recurrent Locally advanced SCC or Unresentable
    - Radiotherapy ± Systemic therapy; or Systemic therapy alone
  3. New regional disease
    - Fully resected regional disease: Adjuvant systemic therapy NOT recommended
    - Resected High-risk regional disease, consider RT ± Systemic therapy
    - For unresectable, inoperable, or incompletely resected disease: RT ± Systemic vs, Systemic Alone
  4. Regional recurrence or distant metastasis
    - Systemic therapy alone ± RT
69
Q

What are the options for systemic therapy/systemic therapy combinations in cutaneous SCC? List 5

A
  1. Cisplatin
  2. Epidermal growth factor receptor (EGFR) inhibitors (Cetuximab, Erlotinib, Gefitinib, Panitumumab)
  3. Cisplatin + 5-FU
  4. Carboplatin ± Paclitaxel
  5. Anti-PD-1 Inhibitors
    - Cemiplimab-rwlc and pembrolizumab are the two preferred by NCCN
    - Nivolumab
    - No age cut off for systemic therapy
70
Q

What is the differential diagnosis for pigmented skin lesions?

A

BENIGN:
1. Spitz nevus
2. Mongolian spot
3. Nevus of Ota
4. Compound Nevus
5. Seborrheic keratoses
6. Other types of Nevi: Junctional (flat), Compound, Intradermal (dome shaped)

MALIGNANT:
1. Malignant melanoma
2. Pigmented BCC
3. Merkel cell carcinoma
4. Kaposi sarcoma

71
Q

What is the differential diagnosis for non-pigmented skin lesions?

A

BENIGN:
1. Keratoses
2. Keratoacanthoma
3. Scar tissue
4. Neurofibroma
5. Squamous papilloma
6. Non-pigmented seborrheic keratoses

MALIGNANT:
1. Desmoplastic melanoma
2. BCC (morphea)
3. SCC
4. Bowen’s disease
5. Dermatofibrosarcoma (keloid looking lesions)
6. Cutaneous T-cell lymphoma

72
Q

Regarding Merkel Cell Carcinoma, discuss:
1. What is it and where in the skin and what cells does it arise from?
2. What are the risk factors? 5
3. What is the histology? What are the stains? 5
4. How does it behave/clinical presentation? What is the rate of recurrence and mets?
5. Treatment?

A

MERKEL CELL CARCINOMA
- Arises from straum basale in epidermis
- Merkel mechanoreceptor is thought to be the originating cell (controversial regarding origin: neuroendocrine vs. ectodermal)

RISKS:
1. Association with Polyoma virus
2. Fair skin
3. Sun exposure
4. UVA therapy
5. Immunosuppression

HISTOLOGY:
1. No epidermal involvement
2. Poorly differentiated
3. Neuroendocrine origin

STAINS: “Stupid NCCN”
1. CK20
2. Synaptophysin
3. Chromogranin
4. NSE
5. Neurofilament protein

BEHAVIOUR:
1. High recurrence rate (45-75%)
2. High lymphatic metastasis rate (50%)
3. 2x recurrence rate of melanoma

TREATMENT:
1. Primary: Wide excision 1-2cm margin
2. Neck:
- N0 = SLNB
- SLNB+ = Metastatic work up followed by either radiation or surgery to the basin
- SLNB- = Consider radiation to the neck
3. Post-op XRT required after wide resection

73
Q

What are melanocytes?
Where are they located?
What cells are they derived from?

A
  • Pigmented cells at the dermal-epidermal junction
  • Produce melanin and package into melanosomes
  • Melanin = pigments skin + hair, provides photoprotection of the skin/eye
  • Derived from neural crest cells (neuroectodermal origin)
74
Q

What are the different kinds of nevi? Name 6

A
  1. NEVOCELLULAR NEVUS (ie. Common Mole)
  2. JUNCTIONAL NEVUS
  3. INTRADERMAL & COMPOUND NEVI
  4. SPITZ NEVUS
  5. CONGENITAL NEVUS
  6. DYSPLASTIC NEVUS
  7. OTHER: BLUE, HALO NEVI
75
Q

What does a Nevocelluar nevus look like?

A
  1. NEVOCELLULAR NEVUS (ie. Common Mole)
    - Simple, small uniform brown macule
76
Q

What does a junctional nevus look like? What is the risk of melanoma transformation?

A
  1. JUNCTIONAL NEVUS
    - Flat, well-circumscribed brown macule, may have darker flecks, even pigmentation
    - Can look like melanoma (biopsy if unsure)
    - 25% transformation risk to melanoma (therefore need to monitor!!)
77
Q

What does an intradermal/compound nevi look like? What is their risk of malignant transformation?

A
  1. INTRADERMAL & COMPOUND NEVI
    - Usually asymptomatic, may be irritated with shaving/rubbed by clothing
    - Variable appearance: flat or raised (well circumscribed), pigmented or not (compound usually hyperpigmented, intradermal is skin colored/slightly erythematous)
    - Never transform
78
Q

What does a spitz nevi look like? What is their risk of malignant transformation?

A
  1. SPITZ NEVUS
    - Melanocytic lesion
    - Often presents as erythematous papule on the head (usually in child/teenage years)
    - If cytologic atypia is seen on histology, requires resection)
79
Q

What does a congenital nevi look like? What is their classification?

A
  1. CONGENITAL NEVUS
    - Big, brown hairy patch, present since birth
    - 5% of the population
    - Classification (Large and Giant 15% transformation risk)
    a. Small < 1.5cm
    b. Medium 1.5-20cm
    c. Large 20-50cm
    d. Giant > 50cm
80
Q

What does a dysplastic nevus look like? What is it associated with?

A
  1. DYSPLASTIC NEVUS
    - Iffy features (approaching ABCDE of melanoma)
    - Biopsy if unsure, surgical removal often recommended
    - Associated with BK Mole Syndrome (CDKN2A gene - encodes for p16)
81
Q

What are the risk factors of melanoma

A
  1. All the risk factors of BCC/SCC (esp. Fitzpatrick 1 - red or blonde, light or blue eyes, fair skin and can’t tan)
  2. Multiple benign nevi (> 20 increases relative risk to 12:1, > 50-100 of any size is high risk )
  3. p16 mutation (CDKN2a tumor suppressor gene mutation)
  4. CDK4 gene mutation
  5. MC1R gene mutation
  6. Family history of melanoma (1st degree) or BK mole syndrome
  7. Congenital nevi (especially large or giant types, > 5% TBSA)
  8. Junctional nevi (at dermal-epidermal junction; 25% transformation risk)
  9. Dysplastic nevi > 3-5 (dysplastic nevus syndrome, Familial atypical multiple mole-melanoma FAMMM syndrome)
  10. Arsenic exposure
  11. Artificial UV or solar UV radiation
  12. Personal history of melanoma

Think: Regular skin cancer risks, syndrome/genetic related risks, and nevus related risks

Note:
- 50-70% of all melanoma arise from pre-existing benign nevi
- Multiple congenital dysplastic nevi
- P16 mutation increases risk
- Unknown primary of melanoma in 1-5%

82
Q

Regarding BK mole syndrome, discuss:
1. What are the different names for this?
2. Genetics and inheritance?
3. What is the clinical presentation?
4. Diagnostic criteria?
5. Prognosis to get melanoma with this syndrome?

A

BK MOLE SYNDROME:
- Aka. Familial Atypical Mole-Melanoma syndrome (FAMM)
- Dysplastic nevus syndrome
- Atypical mole syndrome
- Familial Melanoma

GENETICS/INHERITANCE:
- Autosomal Dominant
- CDKN2A gene mutation (which encodes tumor suppressor p16)

CLINICAL PRESENTATION:
- Multiple, large, congenital and dysplastic nevi
- Often seen in non-sun exposed areas

DIAGNOSTIC CRITERIA: Requires ALL 3 criteria:
1) Malignant Melanoma in one or more first- or second-degree relatives
2) High total body nevi count (often >50) including some of which are clinically atypical (based on ABCD)
3) Nevi with certain histologic features on microscopy (ie. lentiginous pattern, nuclear atypic)

PROGNOSIS:
1. 10 year risk of melanoma - 10%
2. Lifetime cumulative incidence/risk = 100%!!

83
Q

What are the different types of melanoma? List 8

A
  1. SUPERFICIAL SPREADING (Most common 75%)
  2. NODULAR (2nd most common 15-20%)
  3. LENTIGO MALIGNA MELANOMA (4-10%)
  4. MUCOSAL (2% of all H/N melanoma, 50% in nasal cavity)
  5. ACRAL LENTIGINOUS
  6. DESMOPLASTIC/NEUROTROPIC (< 1%, 75% in H/N)
  7. AMELANOTIC
  8. UVEAL MELANOMA
  9. METASTATIC WITH UNKNOWN PRIMARY

Head and Neck Melanoma ~20% of total incidence

84
Q

What does superficial spreading melanoma look like?
Where does it usually arise from?
What is its pattern of spread?

A
  1. SUPERFICIAL SPREADING (Most common 75%)
    - Intermediate prognosis
    - Horizontal superficial spread, Late invasion as it doesn’t travel deep
    - Often from transformation of existing nevus in the 40-50th decade
    - ABCDE criteria
85
Q

What does nodular melanoma look like?
What is its typical pattern of growth?
What is its prognosis?

A
  1. NODULAR (2nd most common 15-20%)
    - Bad prognosis due to vertical growth - BAD AND DEEP
    - Early invasion
    - Blue-red nodule typically
    - DDx: Hemangioma, blue nevus, pyogenic granuloma, pigmented BCC
86
Q

What does lentigo maligna melanoma look like?
What does it usually arise / transform from?
What is its typical spread pattern?
What is its prognosis?

A
  1. LENTIGO MALIGNA MELANOMA (4-10%)
    - Best prognosis
    - Transformation of lentigo maligna (5%)
    - Large ill defined mottled brown patch, asymmetric
    - Lateral spread common
    - Only 30% ever metastasize (usually < 30%)
    - Often extensive peripheral involvement of atypical junctional melanocytic hyperplasia (AJMH)
87
Q

What ae the top 4 most common sites of mucosal melanoma?
Which ones have the best prognosis? Which ones have the worst?

A
  1. MUCOSAL (2% of all H/N melanoma, 50% in nasal cavity)
    - Common sites in order: 1. Nasal 2. Paranasal sinuses, 3. Oral cavity 4. Nasopharynx
    - Nasal cavity and oral cavity best prognosis
    - Paranasal sinuses worst prognosis
88
Q

Who typically gets acral lentiginous melanoma?
Where on the body does it typicall occur?

A
  1. ACRAL LENTIGINOUS
    - Not much in Head/neck, occurs on soles/palms
    - More common in Black/dark skinned people, not from sun
89
Q

How common is desmoplastic melanoma?
What is its common path of spread?
What is its prognosis?

A
  1. DESMOPLASTIC/NEUROTROPIC (< 1%, 75% in H/N)
    - WORST prognosis - highly aggressive (PNI, skull base involvement common, recurrence/spread common - 50% recur)
    - Amelanotic lesions
    - Pure desmoplastic vs. mixed desmoplastic (mixed have high met rates - 22%, pure acts like a regular melanoma)
90
Q

What is Hutchinson’s freckle?
Pathology?
What is the clinical presentation? Where does it usually occur?
What are the chances it becomes melanoma? What if there was a nodule?
What is it associated with?

A

aka. Lentigo maligna, or melanoma in situ

PATHOLOGY:
- Atypical melanocytes
- Radial spread along dermal/epidermal junction
- Focal nests of melanocytic cells

CLINICAL PRESENTATION:
- Irregular, patchy brown skin discoloration
- Usually on face
- Probability of melanoma transformation ~5%
- Presence of a nodule carries likelihood of invasion of 100%

ASSOCIATIONS:
1. Solar damage
2. Atypical melanocytes

Vancouver 92

91
Q

How is tumor / melanoma depth measured?

A

Breslow Depth
- From the Stratum GRANULOSUM layer down

92
Q

Describe the Clark classification

A
  1. Level I: Within epidermis only
  2. Level II: Invasion into papillary dermis (through basement membrane)
  3. Level III: Invasion to papillary-reticular dermis interface
  4. Level IV: Invasion into reticular dermis
  5. Level V: Invasion into subcutaneous tissues
    - 20% nodal spread if sun-induced
    - 50% nodal spread if de-novo
93
Q

What are the different Breslow Depths of the skin and their associated risk of lymph node metastasis?

A
  1. < 0.75mm = 0% risk
  2. 0.75-1.5mm = 25% risk
  3. 1.5-4mm = 50% risk
  4. > 4mm = 75% risk
94
Q

What is the most important factor in overall survival in melanoma?

A
  1. Presence or absence of lymph node metastasis (micro better than macro)
95
Q

What are the ABCDE of melanoma?

A
  1. Asymmetry (lesion itself is asymmetrical)
  2. Border irregularities
  3. Color variation
  4. Diameter ≥ 6mm
  5. Evolution: a lesion that is changing in size, shape, or color, or a new lesion

Other signs:
1. Ulceration
2. Visible skip lesions
3. Palpable lymphadenopathy

96
Q

Describe the general work-up for a melanoma.
What should you keep in mind about biopsy?

A
  1. H&P with attention to locoregional area, draining lymph nodes, complete skin exam (Dermatology)
  2. Biopsy (ideally excision with 1-2mm rim of normal appearing skin and cuff of subdermal fat); if technically not feasible then punch or incision okay. DO NOT SHAVE (affects accuracy); DO NOT use wider initial margins as may affect accuracy of SLNB if you’re going into an area where SLN may be
  3. Ensure ulceration is documented
  4. Neck: SLNB for ≥T1b (highest sensitivity/specificity of any staging modality)
  5. Imaging: Consider CT C/A/P, LDH, PET-CT, CT/MRI Brain/neck - see next card for indications
    - To evaluate specific symptoms; OR
    - Baseline staging if clinically indicated, or SLNB+ lymph nodes (≥ Stage III)
  6. Lab Work (Stage ≥ III)
    - LDH only if distant metastatic disease
    - BRAF mutation testing (modifies chemotherapy regime)
    - BRAF, MEK, C-KIT mutations in >50% of acquired
97
Q

What are the guidelines for imaging of melanoma based on stage?

A

STAGE IA-IIB (T1a-T4a, clinically N0, before SNB)
- None

Stage IIC (T4b, clinically N0, before SNB)
- Consider PET-CT + MRI Brain
- Consider BRAF testing

Stage IIIA: SN+
- Prior to completion dissection - no imaging is necessary (Caveat: if planning groin dissection = morbidity or need to evaluate pelvic nodes)
- May consider PET-CT prior to surgery if doing surgery
- If thick, ulcerated primary, or significant nodal burden: PET-CT + MRI brain prior to potential completion dissection + BRAF testing (ideally reflex testing)

Stage IIIB-D: Palpable, in-transit, recurrent
- PET-CT + MRI Brain
- LDH
- BRAF Testing (ideally reflex testing)

Stage IV:
- PET-CT (esp. oligo-metastatic considering resection)
- MRI Brain
- LDH a MUST and BRAF testing (ideally reflex testing)

98
Q

Regarding PET scans, discuss:
1. What is the mechanism of action of how it works?
2. What are some common indications?
3. Where are normal areas of high activity/always light up? 4
4. Reasons for false positive? 7
5. Reasons for false negative? 2-5

A

MECHANISM OF ACTION:
1. FDG (FluoroDeoxyGlucose) radiotracer is injected (similar to glucose)
2. Gamma radiation taken up by area of high FDG uptake = areas of high metabolic activity
3. Image often combined with CT overlay to improve anatomical localization

INDICATIONS (not exhaustive):
1. Melanoma
2. Unknown primary
3. Staging of poorly differentiated thyroid cancer or hurthle cell carcinoma

NORMAL AREAS OF HIGH ACTIVITY:
1. Brain
2. Liver
3. Kidney
4. Heart

FALSE POSITIVE:
1. Recent biopsy
2. Recent surgery
3. Recent XRT
4. Infection (e.g. tonsillitis)
5. Region of hyperactivity (e.g. thyroiditis)
6. Sarcoidosis
7. ORN

FALSE NEGATIVE:
1. Tumors in region of baseline high activity (variable success)
2. Tumors of low glycolitic activity:
- Adenomas
- Carcinoid
- Low grade lymphoma

99
Q

Describe the classic histopathology of melanoma, and its positive stains

A

PATHOLOGY:
1. “Lentiginous” spread: linear proliferation of melanocytes along basement membrane
2. “Pagetoid” spread: melanocytes floating up through epidermis to surface
3. Invasion: Dark melanin deposits in derms

STAINS:
1. Melan-A
2. HMB-45
3. S-100
4. Tyrosinase
5. SOX10
6. Ki-67 (MIB-1)

100
Q

Define the following:
1. Satellite metastasis
2. Microsatellite metastasis
3. In-transit metastasis

A

SATELLITE:
- Grossibly visible cutaneous or subcutaneous metastases occuring within < 2 cm of the primary melanoma

MICROSATELLITE:
- Microscopic cutaneous and/or subcutaneous metastases found adjacent or deep to the primary melanoma on pathology

IN-TRANSIT METASTASES:
- Cliniically evident dermal and/or subcutaneous metastases identified at a distance >2cm from the primary site, in the region between the primary and first echelon of regional lymph nodes
- Still within the regional nodal bason (otherwise it becomes a distant skin met = M1a)

101
Q

What are 6 methods of identifying occult nodal disease in melanoma?

A
  1. Ultrasound
  2. CT/MRI
  3. SPECT or PET
  4. Elective LN dissection (no benefit found except in 1-2mm thick lesions in patients < 60year of age - MSLT1)
  5. Sentinel LNB (should be offered to Stage IB and above
102
Q

Who should be offered SLNB for melanoma and why? List 7 indications

A
  1. Anyone with ≥ T1b (>5% risk of occult nodal metastasis)
  2. If < 1mm but > 0.5mm, can be considered depending on pathologic features:
    - Age ≤ 42 year old
    - Lymphovascular invasion
    - Head and neck - consider
    - Mitotic index ≥ 1-2/mm^2
    - Deep positive margin
    - Extensive regression to 1mm
103
Q

Describe the findings of the MSLT-1 (Multicentre selective lymphadenectomy trial)

A

OBJECTIVE:
- Patients with cutaneous melanoma following wide local excision, comparing survival between: (1) Observation for development of lymphadenopathy (if develop = ND); and (2) SLNB (if positive = ND)

RESULTS:
- No difference in overall survival
- Subgroup analysis (comparing patients in observation group who went on to develop + neck nodes, vs SLNB+ patients) found a melanoma specific survival benefit for SLNB+ patients with intermediate thickness disease (less nodal recurrence and distant metastasis)

CONCLUSION:
1. Nodal status is the strongest predictor of disease recurrence and melanoma specific death
2. SLNB provides a disease-specific survival benefit in intermediate thickness disease
2. Unclear if SLNB+ patients get the survival benefit of SLNB itself, or from the neck dissection that follows

104
Q

Describe the findings of the MSLT-2 (Multicentre selective lymphadenectomy trial)

A

OBJECTIVE:
- In patients with intermediate thickness melanoma and positive SLNB, comparison between (1) Immediate LN dissection, (2) Observation with U/S, if develop clinically N+ then LN dissection

RESULTS:
- No difference in melanoma specific survival at 3 years, but immediate neck dissection reduced the rate of regional nodal recurrence by 70%

CONCLUSION:
- In patients with SLNB+, completion lymphadenectomy appears to offer no survival advantage but improves local regional disease
- Data slightly conflicts with MSLT1; author’s theory is that the actual volume of nodal disease is often low, and therefore “most patients have all nodal metastasis removed” during SLNB
- Some surgeons do not offer completion neck dissection with SLNB+ (careful discussion required)

NOTE:
Patients that have clinical positive disease is different. They need a neck dissection followed by immunotherapy. Think of it like RAI for thyroid cancer, need to get the big stuff out then immunotherapy to kill the rest

105
Q

What is the false negative rate of sentinel lymph node biopsy in melanoma?

A

5-10%

106
Q

What are the strongest independent poor prognostic indicators in melanoma? 3

A
  1. N+ (MSLT-1)
  2. Elevated LDH (indicator of hypoxic local environment as melanoma outgrows its blood supply)
  3. Depth ? - controversial and debated
107
Q

Describe the steps of a SLNB protocol

A

NUCLEAR MEDICINE
1. Injection lymphoscintigraphy isotope evening before or day of surgery at least 1-2 hours before (more common)
2. 0.2-0.3mL of filtered 99mTc sulfur colloid + isosulfane blue dye is injected intradermally in four quadrants at edge of the lesion, or at either side of the middle of a scar if previous biopsy (6 quadrants if > 2cm lesion)
3. 99mTc phagocytosed by macrophages in lymph nodes, therefore the activity will not “wash out” of lymph nodes
4. Lymphoscintigraphy imaging is done immediately, and can be co-localized with SPECT-CT

PRE-OPERATIVELY:
1. OPTIONAL: Injection of 0.5-1mL of 1% isosulfan blue (lymphazurin; methylene blue) intradermally into the tumor 10-15 minutes prior to skin incision

INTRA-OPERATIVELY:
1. Skin incision in anticipation of future surgery (e.g. Mod Blair for parotid)
2. Remove the primary first (reduces shine through effect from gamma counter)
3. Elevate skin flap, then re-scan area of the gamma counter for precise location
4. Find the LN in the bed, then 10-second count over encountered lymph node - “IN VIVO COUNT” recorded
5. Dissect the lymph node out (don’t crush node - may leak Technetium Tc 99m into surrounding tissues and make counts inaccurate)
6. Remove lymph node and perform two more counts:
- “EX VIVO” 10s count = lymph node itself (usually higher than IN VIVO count)
- 10s wound bed count (should be < 10% than the EX VIVO reading)
- If post-excision count of the tumor bed is > 10% of the EX VIVO SLNB, further dissection indicated

  1. For every LN excised, the take IN VIVO, EX VIVO and post-excision wound bed readings
    - Once the wound bed reading drops under 10% of EX VIVO reading, SLN successfully removed
  2. Nodes sent for permanent pathology
108
Q

What are 3 malignancies where SLNB is indicated?

A
  1. Merkel cell carcinoma
  2. Melanoma
  3. SCC oral cavity
  4. SCC cutaneous also debated
109
Q

What are the resection margins based on melanoma thickness?

A

Tis = 0.5cm
≤ 1mm = 1cm
1-2mm = 1-2cm
> 2mm = 2cm

110
Q

Describe the use of radiotherapy for melanoma. What are its indications? 7

A
  • Melanoma is not a very radio-sensitive tumor
  • May improve local-regional control (88% vs. 75%), but there is no survival benefit
  • Systemic therapies therefore preferred, with better survival benefit

INDICATIONS:
1. Elderly poor candidate for operative resection
2. Extensive facial LMM which would required significant resection
3. Primary for desmoplastic histology with extensive neurotropism
4. Metastatic/recurrent
5. Close margin, ENE+, PNI or large nerve involvement, or in-transit disease
6. Inoperable disease/non-surgical candidate
7. Thick/deep invasion ± satellitosis
8. Unresectable nodal, satellite, or in-transit disease
9. Stereotactic radiotherapy (either radiosurgery or fractionated therapy) is the primary treatment modality for brain mets
10. Palliative intent
11. Multiple regional metastasis
- Parotid > 1LN, any size
- Cervical > 2LN and/or > 3cm

111
Q

What are the indications for systemic therapy in melanoma?

A
  1. Stage III or higher (T3b)
  2. Metastatic
  3. Unresectable disease
112
Q

What are the first line systemic agents for melanoma and their mode of action?

A

IMMUNOTHERAPY:
1. PD-1 Inhibitor (Antibody) monotherapy
- E.g. Pembrolizumab, Nivolumab, Cemiplimab
- Indicated for Stage 3 and greater
- Act as immune checkpoint inhibitors. Checkpoinit proteins (PDL-1 on tumor cells and PD-1 on T cells) keep the immune system in check. When PDL-1 binds to PD-1 it prevents T-cells from killing the cell. If PD-1 is blocked by the checkpoint inhibitor, then the T-cell is able to kill the tumor cell

TARGETED THERAPY (If BRAF V600 activation mutation is present - 65%)
1. Dabrafenib/Trametinib (preferred)
- TKI/MEK inhibtors
- MAP kinase pathway (mitogen activated protein kinase)

  1. Vemurafenib/Cobimetinib
    - Vemurafenib - TKI, inhibits MAP kinase pathway
    - 12% of patients will get cutaneous SCCs as a result of Vemurafenib (severe and undesirable side effects)
113
Q

What are other types of immunotherapy besides PD-1 inhibitors? 4

A
  1. Interferon-alpha 2b
  2. IL-2
  3. Checkpoint inhibitors
  4. Targeted therapies (Tyrosine Kinase inhibitors)
114
Q

Regarding Interferon-alpha 2b, discuss:
1. What is the mechanism of action?
2. What are the indications? 6
3. What is the regimen?
4. What are the risks? 5
5. What are the benefits?

A

MECHANISM OF ACTION:
1. Biologic response modifier
2. Direct anti-tumor effects
3. Increase host anti-tumor immune response (T-cells, NK cells, etc.)

INDICATIONS:
1. Stage III + (T4 or N+) - can be used as adjuvant treatment
- Still indicated, but seemingly less popular now with the newer checkpoint inhibitors and targeted tyrosine kinase inhibitors
2. Thickness ≥ 4mm
3. In transit metastasis
4. Positive SLNB
5. Clinical nodes
6. Nodal recurrence
7. Unknown primary

REGIMEN:
1. High dose IV - 20 million units (MU) / m^2 - 5d/wk x 4 weeks, then
2. Low dose IV 10 MU SC 3d/wk x 48 weeks (maintenance)

RISKS (50% need dose reduction due to intolerable side effects):
1. Severe fatigue
2. Psych (depression, suicide)
3. MI, arrhythmias
4. Liver
5. Myelosuppression

BENEFIT:
1. 10% relapse-free survival increase
2. LImited overall survival benefits

115
Q

Regarding IL-2 Immunotherapy, discuss:
1. What is the mechanisms of action?
2. What are the indications in melanoma?
3. What are the risks?
4. What are the benefits?

A

MECHANISM OF ACTION: Boosts host immune system by:
1. Activating T-cells, NK, monocytes, cytokines, etc.
2. No direct anti-tumor effects

INDICATIONS:
1. Stage 4 (M+)

RISKS (Potentially severe and lethal - only for the healthiest patients):
1. MI, arrhythmia
2. Resp issues
3. Hypotension
4. Capillary leak syndrome
5. Nephrotoxicity
6. Hepatic toxicity
7. Sepsis
8. Anemia
9. Thrombocytopenia

BENEFIT:
1. 10% Response Rate

116
Q

Regarding Checkpoint Inhibitors for Melanoma, discuss:
1. How do these work?
2. What are the examples?
3. What are the indications?

A

CHECKPOINT INHIBITORS:
- Checkpoint inhibitors block key immune checkpoinits, including PD-1 and CTLA-4, and therefore kick the immune system into hyperdrive (by blocking the proteins that typically keeep the immune system in check)
- “-mabs”

  1. Anti-PD-1 Monoclonal antibody agents = Nivolumab (Anti-PDL-1 = Pembro) = “Programmed cell death 1”
  2. Anti-CTLA-4 monoclonal antibody agents = Ipilimumab = Cytotoxic T-lymphocyte associated protein 4
    - Both have been shown to prolong progression-free and overall survival

INDICATIONS:
1. Stage 3+ disease
2. Nivolumab recommended over Ipilimumab, as it has better efficacy and less toxicity than ipilimumab
- Combination therapy is being trialled but definitely has more toxicity

117
Q

Regarding Targeted Therapies and Tyrosine Kinase inhibitors for melanoma, discuss:
1. What is the pathway they effect?
2. What are the example agents? What are the benefits?
3. Indications?
4. Side effects?
5. What is the role of Imatinib?

A

TYROSINE KINASE INHIBITORS
- MAP Kinase (MAPK) pathway inhibitors
- ≥50% of melanoma is positive for BRAF V600 (which upregulated MAPK)
- “-nibs”

EXAMPLES:
1. Multiple agents target BRAF V600, including Vemurafenib, Dabrafenib
2. Agents often combined with MEK inhibitors (mitogen-activated protein kinase kinase) - Cobimetinib, Trametinib
- Improves survival
- Reduces development of treatment resistance (often seen after 6-7 months in single agent therapy
- Vemurafenib is combined with Cobimetinib “VC”
- Dabrafenib is combined with Trametinib “DT”

INDICATIONS:
1. Stage 3+ with BRAF V600 activating mutation
- Increase progression-free survival
- Increase overall survival

SIDE EFFECTS:
1. Vemurafenib - arthralgia, cutaneous SCC, rare complication of cardiac tamponade

IMATINIB (GLEEVEC):
- Patients with activating mutations in KIT (c-KIT, also encodes tyrosine kinase) show meaningful response to Imatinib in small trials
- KIT mutation in ~15% melanoma
- Short duration of benefit
- Indications: Metastatic or unresectable disease

118
Q

What additional systemic therapies are there for metastatic or unresectable melanoma?

A
  1. Ipilimumab
    - Binds to Cytotoxic T-lymphocyte associated antigen 4 (CTLA4), blocks this inhibitory signal to allow the cytotoxic T-cell to destroy cancer cells
  2. High dose IL-2
  3. Imatinib
    - BCR-ABL (gene)/cKIT tyrosine kinase inhibitor
119
Q

Discuss the role of cytotoxic chemotherapy with melanoma. What are the agent types and indications?

A
  • Melanoma not very chemosensitive (< 20% response rate)
  • No survival benefit

OPTIONS:
1. Dacarbazine (only chemo agent approved for Stage IV; response 10-20%, often used in combo with others)
2. Temozolomide
3. Paclitaxel
4. Carboplatin

INDICATIONS (essentially palliative):
1. Advanced (metastatic or unresectable) disease that has failed trial of other systemic options (immunotherapy, targeted therapy)
2. Advanced stage IV disseminated melanoma

120
Q

Discuss the role of Oncolytic Virotherapy in melanoma. How does it work?

A
  • “Talimogene Laherparepvec” (T-VEC)
  • Attenuated HSV virus, that expresses GM-CSF (Granulocyte-macrophage colony-stimulating factor)
  • Injection into unresectable tumor causes tumor lysis and enhances immune response (local tumor cell death, increase systemic clearance of tumor cells at uninjected sites)
121
Q

Discuss the 5-year melanoma overall survival

A
  • < 0.7mm = 98%
  • > 3mm = 53%
  • Recurrence will occur 70% within 2 years, 80% within 3 years
122
Q

Discuss the follow up schedule for melanoma

A
  • Stage IA: Annual Exam
  • Stage IB and above: standard HN follow up regimen and annual LDH level; CBC ± imaging if suspicious clinical features arise
123
Q

What is the rate of positive sentinel nodes in all comers?
Desmoplastic melanoma?
What is the false negative rate?

A

All comers = 20%
Desmoplastic = 5-10%
False negative = 5%

124
Q

What is the typical route of spread for Desmoplastic melanoma?

A

Perineural invasion (like adenoid cystic carcinoma)

Head and Neck (15 decks)

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