DermatologyTier 1Disease (DEADMAN)

Cutaneous oncology - squamous cell carcinoma

Description

Malignant proliferation of epidermal keratinocytes with dermal invasion
Second commonest skin cancer after BCC, but responsible for most keratinocyte-cancer deaths
Arises from a field of UV-damaged skin -> the whole field is at risk, not just the lesion

Spectrum


Actinic keratosis	Rough scaly macule on sun-damaged skin; ~0.1-1%/lesion/yr progression
SCC in situ (Bowen disease)	Full-thickness dysplasia, intact basement membrane; well-demarcated scaly erythematous plaque
Invasive SCC	Breaches basement membrane; can metastasise
Keratoacanthoma	Rapid growth over weeks, central keratin plug; treat as well-differentiated SCC - do not observe

Appearance

Firm, tender, hyperkeratotic or ulcerated nodule on sun-exposed skin
Pain or tenderness suggests perineural invasion
Head/neck, dorsal hands, forearms, lower legs (women), lip and ear (high-risk sites)

Australia has the highest incidence in the world - >500 per 100,000/yr
2 in 3 Australians develop a skin cancer by age 70
M>F (~2:1); incidence rises steeply after 50
Fitzpatrick I-II, outdoor occupation, cumulative lifetime UV
Organ transplant recipients: 65-250x increased risk, SCC:BCC ratio inverts to ~4:1

Cumulative UVB -> pyrimidine dimers -> UV-signature C->T and CC->TT mutations
- TP53 mutation is the earliest and commonest event (present in actinic keratoses)
- Then CDKN2A, NOTCH1/2, RAS
Among the highest tumour mutational burdens of any cancer -> high neoantigen load -> exquisite sensitivity to PD-1 blockade

Risk factors

UV: cumulative exposure, sunburn, solaria, PUVA (dose-dependent)
Immunosuppression: solid organ transplant (azathioprine, ciclosporin; sirolimus/everolimus reduce risk), CLL, HIV, chronic lymphoproliferative disease
Drugs: BRAF inhibitors (vemurafenib, dabrafenib) - paradoxical MAPK activation in RAS-mutant keratinocytes; abolished by adding a MEK inhibitor; voriconazole, hydrochlorothiazide, azathioprine
Chronic wound/scar - Marjolin ulcer (burn scar, sinus tract, chronic ulcer; aggressive)
HPV - beta-HPV in immunosuppressed; HPV 16 in periungual and anogenital SCC
Arsenic, ionising radiation, tar
Genodermatoses: xeroderma pigmentosum, oculocutaneous albinism, epidermolysis bullosa (recessive dystrophic)

Biopsy

Excisional or deep incisional/punch - shave biopsy may not reach the depth needed to assess invasion and thickness
Report: differentiation, depth/thickness, perineural invasion, lymphovascular invasion, margins

High-risk features - drive everything downstream

Diameter >=20 mm (or >=10 mm at high-risk sites)
Thickness >6 mm or invasion beyond subcutaneous fat
Poorly differentiated
Perineural invasion, particularly of nerves >=0.1 mm
Site: ear, lip, temple, periocular, genitalia; "mask areas" of the face
Recurrent tumour
Immunosuppression
Arising in a scar, chronic ulcer or previously irradiated skin
Staging systems: Brigham and Women's (BWH) T-stage outperforms AJCC 8 for cutaneous SCC

Nodal assessment

Palpate regional nodes in every case
Ultrasound +/- FNA for suspicious nodes
CT/MRI if high-risk, nodal, or clinical perineural symptoms (MRI for skull-base perineural spread)
Sentinel node biopsy is not routine and has no proven survival benefit in cutaneous SCC

Risk-stratified. Surgery is curative in the great majority; the value-add is identifying the minority who are not.

A. Precursor lesions

Actinic keratosis: cryotherapy for isolated lesions; field treatment for multiple - 5-FU, imiquimod, ingenol (withdrawn), photodynamic therapy
Bowen disease: cryotherapy, 5-FU, imiquimod, PDT, curettage, or excision
Any AK that is tender, thickened, bleeding or enlarging -> biopsy

B. Low-risk invasive SCC

Surgical excision with 4-6 mm clinical margin to subcutaneous fat
Curettage and cautery only for small, well-differentiated, low-risk trunk/limb lesions

C. High-risk SCC

Wider excision (6-10 mm) or Mohs micrographic surgery
- Mohs preferred for face, ear, lip, periocular, recurrent tumour, ill-defined margins, perineural invasion
Adjuvant radiotherapy if: positive/close margins not re-excisable, extensive perineural invasion, nodal disease with extracapsular extension
Definitive radiotherapy if inoperable or patient unfit
All high-risk cases to a skin cancer MDT

D. Nodal disease

E. Very high-risk after surgery + radiotherapy

Adjuvant cemiplimab - C-POST showed ~68% reduction in recurrence or death; now a category 1 / standard-of-care option after resection with negative margins plus adjuvant RT in extremely high-risk disease

F. Locally advanced or metastatic

Cemiplimab (anti-PD-1) - first-line systemic therapy; response ~45-50%, durable
- Pembrolizumab an alternative
- *Caution/contraindication in solid organ transplant recipients - rejection risk* - discuss with transplant unit; consider reduced immunosuppression + mTOR switch instead
Cetuximab or platinum-based chemotherapy where immunotherapy contraindicated
Neoadjuvant cemiplimab for resectable stage II-IV shows high pathological complete response - increasingly used in MDT settings

G. Everyone - field and follow-up

Rigorous sun protection; primary prevention still reduces new lesions in the already-affected
Nicotinamide 500 mg bd reduces new non-melanoma skin cancers ~23% in high-risk patients
Transplant recipients: annual-to-quarterly dermatology surveillance; switch azathioprine -> mycophenolate, or ciclosporin -> sirolimus/everolimus; minimise net immunosuppression
Skin examination schedule: 3-6 monthly for 2 years for high-risk, then 6-12 monthly; total skin + nodes lifelong

Cumulative UV exposure; Fitzpatrick I-II
Solid organ transplantation and other chronic immunosuppression; CLL
BRAF inhibitor therapy (vemurafenib, dabrafenib) - risk abolished by adding a MEK inhibitor
Voriconazole (long-term, lung transplant), hydrochlorothiazide, azathioprine
PUVA, ionising radiation, arsenic, tar
Chronic wounds, burn scars, sinus tracts, recessive dystrophic epidermolysis bullosa, discoid lupus, lichen sclerosus (genital)
HPV (beta types in immunosuppressed; HPV16 periungual/anogenital)
Xeroderma pigmentosum, albinism
A prior keratinocyte cancer is the strongest predictor of the next one

>95% cured by adequate excision
Overall metastatic rate ~2-5%; rises to 10-30% with high-risk features
- Ear, lip, immunosuppression, thickness >6 mm, perineural invasion, poor differentiation
Metastasis is lymphatic first (regional nodes, parotid for facial lesions), lung later
Most recurrences and metastases occur within 2 years -> that is where surveillance is concentrated
~50% of patients develop a second keratinocyte cancer within 5 years
Nodal disease: 5-year survival ~50-70% with surgery + radiotherapy
Perineural invasion - may present with numbness, paraesthesia, facial weakness or diplopia; skull-base spread carries poor prognosis
Complications: local destruction of ear/nose/eyelid, functional and cosmetic loss, immunotherapy-related irAEs, graft rejection if PD-1 used post-transplant

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