KEY NOTES CHAPTER 2: SKIN AND SOFT TISSUE LESIONS - Malignant non-pigmented skin lesions.

Question 0

What is aetiology of NMSCs?

Answer 0

1. Premalignant conditions: Bowen’s disease, AKs, sebaceous naevi, leukoplakia, erythroplakia.
2. Radiation: UVA, UVB, ionising radiation.
3. Immunosuppression
4. Chronic wounds (Marjolin’s ulcer).
5. Toxins (soot, arsenic).
6. Genetic:
   - Xeroderma pigmentosum
   - Albinism
   - Fair skin Type I&II.

Question 1

What are the main types of non-pigmented skin cancers?

Answer 1

∘ BCC
∘ SCC
∘ Merkel cell carcinoma (MCC)
∘ Sebaceous carcinoma

NPSC is the most common malignancy in the Western world.

Question 2

How did Fitzpatrick classify skin type?

Answer 2

• Fitzpatrick classified skin type based on colour and response to UV light:
∘ Type I: pale white skin, always burns, never tans.
∘ Type II: white skin, always burns easily, tans minimally.
∘ Type III: light brown skin, burns moderately, tans uniformly.
∘ Type IV: moderate brown skin (Mediterranean complexion), burns minimally, always
tans well.
∘ Type V: dark brown skin (Indian complexion), rarely burns, tans profusely.
∘ Type VI: deep brown to black skin, never burns.

Question 3

What is BCC?

Answer 3

• A slow-growing, locally invasive malignant epidermal skin tumour.
• Usually emerges from keratinocyte stem cells in hair follicles, sebaceous glands or interfollicular basal cells.
• Most common neoplasm in Caucasians
• 85% occur after 40 years of age.
• 80% occur in sun-exposed sites of the face, head and neck, arms and dorsal hands.
• Over 300 cases of metastatic BCC are reported.

Question 4

What is the pathogenesis of BCC?

Answer 4

Acquired
• Most cases are sporadic.
• Associated with sun exposure (UVB) -> gene mutations e.g. p53 and PTCH1 tumour suppressor genes.

Genetic
• Gorlin’s syndrome and xeroderma pigmentosum - same gene mutations.

Question 5

What histological findings are commonly found in BCCs?

Answer 5

• Sheets or nests of small round basophilic cells.
• Peripheral palisading of nuclei at the margins of cell nests.
• Inflammatory infiltrate and ulceration.

Question 6

How are BCCs classified?

Answer 6

26 histopathological types described by Wade and Ackerman (1978).

Most common (90% of all BCCs)
∘ Nodular (30-75%)
∘ Superficial (10-15%)
∘ Infiltrative (10%).

Question 7

What are the prognostic indicators for recurrence following treatment?

Answer 7

Factors increasing risk of local recurrence can be subclassified into:

1. Patient factors
2. Macroscopic features
3. Microscopic features.
4. Patient factors
   • Immunosuppression.
5. Macroscopic features
   • Increasing tumour size.
   • Location: central face, especially around eyes, nose, lips and ears.
   • Poorly defined lesions.
6. Microscopic features
   • Histological subtypes - infiltrative and morphoeic.
   • Perineural or perivascular involvement.
   • Recurrent lesions.

Question 8

What is basal cell naevus syndrome?

Answer 8

• Aka Gorlin’s / Gorlin-Goltz syndrome.
• Autosomal dominant; associated with germline mutations in PTCH gene.

• Characterised by:

• early onset multiple BCCs.
• Palmar and plantar pits.
• Odontogenic keratocysts, mandible > maxilla.
• Bifid ribs.
• Calcification of falx cerebri
• Overdevelopment of supraorbital ridges, mild hypertelorism.
• Learning difficulties ~ 5%.

• Associated with congenital blindness, hypogonadism, ovarian fibromas (75% women), CNS tumours e.g. medulloblastoma.

Question 9

What are the different modalities of treatment for BCCs?

Answer 9

Can be divided into:

Non-surgical

Surgical:
∘ Destructive - curettage and cautery, cryotherapy, laser
∘ Nondestructive - excision.

Question 10

What are the non-surgical treatments?

Answer 10

Imiquimod (Aldara®)
• Topical immune response modifier for superficial BCCs.
• Binds to Toll-like receptor-7 on macrophages and dendritic cells to induce production of
interferon-α, TNF-α and interleukins.
• This promotes a cell-mediated immune response.
• It also decreases expression of Bcl-2, leading to tumour apoptosis.
• 6 week course, 5 days/wk.
100% cure rate for sBCC, 75% nBCC, 60% iBCC.

5-Fluorouracil (Efudix®)
• Applied topically to low-risk superficial BCCs.
• 5-FU inhibits thymidylate synthetase and disturbs DNA synthesis, leading to cell death.

Vismodegib (Erivedge®)
• Systemic inhibitor of hedgehog signalling pathway.
• Used for metastatic BCC, or locally advanced disease not amenable to surgery/
radiotherapy.

Question 11

What are the destructive surgical treatments for BCC?

Answer 11

Biopsy confirmation of low-risk BCC required prior to treatment, as no pathology specimens are obtained from destructive treatment.

1. Curettage and cautery
   • Best suited for small, well-demarcated tumours.
   • Wound left to heal by secondary intention.
   • Low risk BCC: 92.3% cure rate.
2. Cryotherapy
   • Repeated freeze-thaw cycles cause ice crystals to form and tumour cell ischaemia by vascular stasis.
   • Low risk BCC: 99% 5 yr cure rate.
   • High risk BCC: 8% recurrence with mean follow-up 5yrs.
3. Radiotherapy
   • 5yr cure rates similar to excision (91.3% for primary BCC and 90.2% for recurrent BCC); excellent early cosmetic results.
   • Atrophic changes occur over time - unsuitable for treatment of young patients.
   • Useful for elderly patients unsuitable for surgery.
4. Photodynamic therapy (PDT)
   • Photosensitising chemical, e.g. MAL (methyl aminolevulinate - Metvix®) makes tumour more susceptible when treated with a light source.
   • Efficacy depends on how deeply MAL penetrates tumour.
   • Bright light causes MAL to generate oxygen radicals that induce cell death (painful).
   Clearance rates at 3mths: 93% for sBCC, 82% for nBCC, 82% and 67% at 24mths.
5. CO2 laser
   • Controversial treatment with mixed results; best for superficial BCCs.
   • Combining CO2 laser with PDT is a new approach, with clearance rates comparable to surgery (less painful as short burst of laser).

Question 12

How should BCCs be surgically excised?

Answer 12

Deep margin should be into subcutaneous fat minimum.

Peripheral margins for:
• Well-defined lesions <2cm:
∘ 3mm clears tumour in 85% cases.
∘ 4-5mm clears tumour in 95%.

• Large or poorly defined lesions, e.g. morphoeic BCC:
∘ 3mm clears tumour in 66%.
∘ 5mm clears tumour in 82%.
∘ 13-15mm clears tumour in >95%.

• Up to 2% of BCCs reported as having clear margins will recur.
∘ May be due to sampling error during vertical sectioning (‘bread-loafing’ - only ~40% of specimen margin is assessed).

Telfer et al., BAD guidelines 2008.

Question 13

What is Mohs micrographic surgery?

Answer 13

Dr Frederic Mohs (1938): medical student at University of
Wisconsin-Madison.
• High cure rates with maximal preservation of normal tissue.
• Labour intensive; reserved for high-risk lesions in cosmetic areas on face.
• Assesses entire specimen margin intraoperatively.

1. Obvious tumour mass removed with no regard for clear margins, leaving saucer-shaped defect.
2. Peripheral margins of defect marked at 3, 6, 9 and 12 o’clock. Entire
   margin is excised with ≈2mm margin.
3. Specimen (like a shallow bowl), is squashed flat and rapidly frozen and sectioned parallel to surface of skin.
4. Sections contain skin from periphery and fat from base of wound. Entire surgical margin is assessed simultaneously.
5. Residual tumour is mapped to orientation markings; further excision is targeted to those zones.
6. The process is repeated with further excision specimens until clear margins obtained.

Question 14

What is the management for incompletely excised BCCs?

Answer 14

• ~4-7% of BCCs are incompletely excised (esp. inner canthus, alar base and external auditory meatus).
• Possible reasons for incomplete excision in high risk areas:
- Invasion can proceed down natural embryonic fusion lines?
- BCCs overlying embryonic fusion lines more likely to be infiltrative?
- Excision and reconstruction is more complex?

• Risk of recurrence is highest when:
∘ Both lateral and deep margins involved
∘ Recurrent BCCs
∘ Radio-recurrent lesions.

• Re-excision is recommended:
∘ Critical midfacial sites
∘ Deep margin involvement
∘ Aggressive histological subtypes
∘ Under flap or skin graft reconstructions (might mask recurrence).

Question 15

…

Answer 15

• Treatment is controversial:

1. Mohs
2. ‘Slow-Mohs’ (but margins are assessed by breadloafing).
3. Observation
   - laterally incomplete lesions: 17% recur.
   - deep incomplete margin: 33% recur.

• Re-excision shows residual tumour in only 55% of cases using Mohs.

• UK guidelines: wider excision of 5-10mm, or Mohs.
• Radiotherapy is effective in preventing recurrence following incomplete excision.

Question 16

What is SCC and its epidemiology?

Answer 16

• Malignant tumour of keratinising cells of epidermis or its appendages.
• Second most common skin cancer; 20% of all cutaneous malignancies.
• Commoner in males - lifetime risk 9-14%; 4-9% in women (US data).

Question 17

What are the risk factors for developing SCCs?

Answer 17

• Chronic exposure to UV / other radiation - sunbeds, outdoor workers.
• Premalignant lesions - keratin horns, AK, leukoplakia, Bowen’s disease.
• Smoking - particularly for lip SCC.
• Immunodeficiency - recipients of organ transplants.
• Chronic wounds and inflammation - scars, burns, ulcers, psoriasis.
• Toxins - arsenic.
• Genetic predisposition - albinism, xeroderma pigmentosum.
• Viral infection - HPV, herpes simplex.

Question 18

How do SCCs look histologically?

Answer 18

• Dysplastic epidermal keratinocytes invade through basement membrane into dermis.
• The degree of keratinisation is variable - presence of keratin pearls is characteristic.

Question 19

What are the prognostic factors for SCC?

Answer 19

SCCs are prone to local recurrence (3-23% depending on primary) and metastases.

Adverse prognostic factors:

• Patient factors: immunosuppression.
• Macroscopic features (site, size)
• Microscopic features (depth of invasion, differentiation, subtype)
• Previous treatment and modality (Mohs lowest risk).

Question 20

What macroscopic features are risk factors for local recurrence and metastatic spread?

Answer 20

Anatomical site
• Sites most prone to metastatic spread:
1. Areas of radiation or thermal injury, chronic draining sinuses, chronic ulcers, chronic
inflammation or Bowen’s disease - 38%.
2. Non-sun-exposed sites (e.g. perineum, sacrum, sole of foot) - 38%.
3. Lip - 14%.
4. Ear - 9%.
5. Sun-exposed sites, excluding lip and ear - 5% (the only category considered ‘low
risk’).

Tumour size
• >2 cm diameter twice as likely to recur locally and three times as likely to metastasise
as smaller tumours.

Question 21

What microscopic features are risk factors for local recurrence and metastatic spread?

Answer 21

Depth of invasion
• Tumours >4mm depth (excluding surface layers of keratin) or extending into subcutaneous fat.
• Tumours with perineural involvement, lymphatic or vascular invasion.

Histological differentiation/Broders grade
• Broders grade is based on ratio of differentiated to undifferentiated cells:
∘ Grade 1 - ratio of 3:1
∘ Grade 2 - ratio of 1:1
∘ Grade 3 - ratio of 1:3
∘ Grade 4 - No tendency towards differentiation.
• Poorly differentiated (Broders 3 and 4) have poorer prognosis: >2× local recurrence rate and 3× metastatic rate compared to Broders 1 and 2.

Histological subtype
• Acantholytic, spindle and desmoplastic have poorer prognosis than verrucous subtype.

Question 22

What is the T staging for SCC?

Answer 22

Primary tumour (T)
• Tis: carcinoma in situ.
• T1: tumour ≤2 cm with <2 high-risk features.
• T2: tumour >2 cm or tumour any size with ≥2 high-risk features.
• T3: tumour with invasion of maxilla, mandible, orbit or temporal bone.
• T4: tumour with invasion of skeleton (axial or appendicular) or perineural invasion of
skull base.

Question 23

What are the high-risk features for T staging?

Answer 23

• Depth/invasion
∘ >2mm thickness
∘ Clark level ≥ IV
∘ Perineural invasion

• Anatomic location
∘ Primary site ear
∘ Primary site non-hair-bearing lip

• Differentiation
∘ Poorly differentiated or undifferentiated.

Question 24

What is the NM staging for SCC?

Answer 24

Regional lymph nodes (N)
• N0: No regional lymph node metastasis.
• N1: Metastasis in a single ipsilateral lymph node ≤3 cm.
• N2a: Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm.
• N2b: Metastasis in multiple ipsilateral lymph nodes, none >6 cm.
• N2c: Metastasis in bilateral or contralateral lymph nodes, none >6 cm.
• N3: Metastasis in a lymph node >6 cm.

Distant metastasis (M)
• M0: No distant metastases
• M1: Distant metastases.

Question 25

How are SCCs treated?

Answer 25

Surgery: gold standard
• Recommended peripheral margins:
∘ 4+mm for well-defined, low-risk tumours <2 cm.
∘ 6+mm margin for higher risk tumours, including:
- >2 cm
- Moderate, poor or no differentiation
- Extending into subcutaneous tissue
- Ear, lip, scalp, eyelids or nose.
• Larger, indistinct tumours should be excised with larger margins or Mohs surgery.

Referral to a skin cancer MDT.
• Patients with high-risk SCC and/or involved lymph nodes should be reviewed by a specialist
MDT for multimodality treatment planning.

Radiotherapy
• Cure rates >90%.

Other treatment options
• Cryotherapy, curettage and cautery (low-risk lesions).

Question 26

What is Merkel cell carcinoma (MCC)?

Answer 26

• Rare, aggressive, primary cutaneous neuroendocrine carcinoma.
• Merkel cells are mechanoreceptors of neural crest origin.

Epidemiology
• Estimated annual incidence 1 in 500,000.
• Commoner in elderly Caucasians; M=F.

Question 27

What is the aetiology of MCC?

Answer 27

• 80% thought to be caused by Merkel cell polyomavirus (MCPyV).
• Also linked to previous radiation exposure and B-cell lymphoma.

Question 28

What are the clinical features of MCC?

Answer 28

• Present as rapidly growing, firm, painless purple-red nodules.
• Most prevalent in sun-exposed sites:
∘ 50% in head and neck; 35% in extremities.
• Up to 15% have involved lymph nodes on presentation.
• Up to 83% eventually develop nodal disease or distant metastases.

Question 29

How is MCC diagnosed?

Answer 29

• Light microscopy (similar to other undifferentiated small-cell neoplasms e.g. lung).
• Three histological types:
1. Classic trabecular (10%)
2. Intermediate (80%)
3. Small-cell variant (10%).

• Immunohistochemistry: Cytokeratin 20 and neurofilament protein
• CXR: exclude lung primary with secondary skin metastasis.

Question 30

What is the prognosis for MCC?

Answer 30

• MCCs are locally aggressive, with a higher rate of regional metastasis than melanoma.
• 5-year survival for primary MCC is: 
- 75% for primary tumour, 
- 59% for local recurrence
and/or lymph node metastases, 
- 25% for distant metastases.

• Factors adversely affecting prognosis:
∘ Increasing disease stage
∘ Male sex
∘ Lesions in head and neck or trunk
∘ Immunosuppression
∘ Small-cell variant, undifferentiated
∘ Increasing tumour thickness.

Question 31

What is the treatment for MCC?

Answer 31

• SSMDT
• WLE 2-3 cm margins: decrease risk of local recurrence.
• ? Elective neck dissection (55% develop regional lymph node metastases).
• ? Adjuvant radiotherapy primary site and likely lymphatic basins.

• Palliative chemotherapy

Question 32

What is sebaceous carcinoma?

Answer 32

• Rare and aggressive tumour arising from sebaceous glands.
• Presents as yellow or orange nodule.
• ~ 75% (particularly elderly, females and Asians), occur in periocular region (poor prognosis). Often resemble chalazion.

• Prone to local and distant recurrence.
∘ Local recurrence ~36%, even with Mohs surgery.
• May present as part of Muir-Torre syndrome: refer to gastrointestinal MDT for
screening.
• Treatment: WLE.