Cutaneous squamous cell carcinoma

Meet the patient

A 74-year-old retired builder has a crusted, hyperkeratotic nodule on his bald scalp that has been growing for four months and now bleeds when he combs his hair. The surrounding skin is weathered with telangiectases and mottled dyspigmentation, and he has half a dozen rough, gritty patches alongside it. He has never worn a hat.^[2][4]

That scalp tells the whole story of SCC. The gritty patches are actinic keratoses, the field around them is field cancerization, and the crusted nodule is the lesion that has crossed the basement membrane into invasive SCC. Two questions decide his next step: is this high-risk? (site, size, depth, differentiation, perineural signs) and what operation? (excision versus Mohs). Hold those two and the topic falls into place.^[1]

The numbers you meet this cancer by

^[1]

SCC is the second commonest skin cancer and the commonest keratinocyte carcinoma that can kill. In the United States more than a million cases are diagnosed a year, and — the statistic examiners love — the absolute number of deaths from cutaneous SCC now equals or exceeds deaths from melanoma and from leukaemia. Low per-tumour mortality hides a vast public-health burden because the volume is enormous.^[2][6]

What SCC is — one spectrum, three stages, one basement membrane

Cutaneous SCC is an invasive malignant proliferation of atypical keratinocytes that breaches the basement membrane. It does not appear from nowhere; it is the final stage of a spectrum — actinic keratosis (AK) → SCC in situ (Bowen's disease) → invasive SCC — all riding on the same UV-damaged field. The basement membrane is the line: while atypia is confined to the epidermis the lesion is premalignant or in situ; the moment atypical keratinocytes cross into the dermis, it is invasive SCC and the metastatic risk begins.^[2][6]

Histological subtype changes behaviour, so read the report, not just the diagnosis:^[3]

Conventional SCC dominates clinically (over 80 percent); verrucous, desmoplastic and acantholytic subtypes carry disproportionate metastatic risk and demand high-risk management even when they look indolent.^[1]

Etymology for viva gold: Bowen's disease honours John Bowen, the American dermatologist who described SCC in situ in 1912. The eponym survived because the lesion — a fixed, scaly, sharply demarcated red patch — is clinically nothing like a nodule, yet histologically it is one cell layer away from invasive cancer.^[3]

How common, who, and the risk amplifiers

Cumulative UV on fair skin is the engine; immunosuppression is the multiplier. The lifetime risk in fair-skinned populations exceeds 15 percent, and the typical patient is an older man, Fitzpatrick I–II, with decades of outdoor work and the solar elastosis to prove it. Intense intermittent exposure (sunburns), PUVA, indoor tanning and equatorial residence all add risk.^[5][6]

Immunosuppression is the second great amplifier. Solid-organ transplant recipients carry a 65- to 250-fold higher incidence, and the SCC:BCC ratio inverts — from about 1:4 in the immunocompetent to about 4:1 in transplant recipients. Their SCCs are more numerous, more aggressive, earlier, and recur more often; heart and lung recipients (heavier immunosuppression) fare worst. Chronic lymphocytic leukaemia, HIV with CD4 under 200, iatrogenic immunosuppression (azathioprine, ciclosporin, TNF and JAK inhibitors), and chronic GVHD all add smaller excesses.^[1][2][6]

Chemical and physical carcinogens. Arsenic (groundwater, pesticides, Fowler's solution) gives arsenical keratoses on palms and soles and a Bowenoid field. Ionising radiation (historical radiotherapy for acne, tinea capitis, ankylosing spondylitis, Hodgkin lymphoma; occupational exposure) and UVB/PUVA produce SCC after a 20- to 40-year latency. Chronic thermal injury (kangri-burn cancer in Kashmir, peat-fire and Kang cancers) works the same way.^[1]

Chronic scars and chronic inflammation are textbook SCC substrates — burn scars, osteomyelitis sinuses, chronic venous or arterial ulcers, vaccination scars, acne conglobata scars, pilonidal sinuses, pressure sores and any chronically draining wound. These are the classic Marjolin ulcer substrates: decades of latency, aggressive behaviour, metastatic potential up to 30 percent. Lichen sclerosus (anogenital), lichen planus (oral, vulvovaginal) and discoid lupus are scarring inflammatory dermatoses with documented SCC transformation.^[1]

Genetic susceptibility magnifies risk dramatically: xeroderma pigmentosum (nucleotide-excision-repair defect, 10,000-fold NMSC risk in childhood), epidermodysplasia verruciformis (EVER1/EVER2, beta-HPV-driven), oculocutaneous albinism, Rothmund–Thomson, Bloom and Fanconi syndromes. HPV drives SCC especially in the immunosuppressed (beta-HPV 5, 8 in transplant and epidermodysplasia disease; alpha-HPV 16, 18 in anogenital, oropharyngeal and periungual SCC). Tobacco adds risk, synergistically, to lip and oral SCC.^[1][6]

The face-off — who is at the dangerous end:^[1]

^[1]

Pathophysiology — UV, TP53, and the field

UV-driven mutagenesis is the molecular cornerstone. UVB (290–320 nm) is directly absorbed by DNA, forming cyclobutane pyrimidine dimers and 6-4 photoproducts; the canonical UV-signature mutations are C to T and CC to TT transitions at dipyrimidine sites. TP53 is mutated in 60–80 percent of cutaneous SCCs (and in 50–80 percent of precursor AKs) — loss of the G1/S checkpoint and resistance to apoptosis let damaged keratinocytes clonally expand.^[3][7]

The rest of the driver map sits alongside TP53:^[1]

• NOTCH1 and NOTCH2 (tumour-suppressor receptors) are inactivated in about 60 percent — remarkably high, placing Notch loss beside TP53 as a defining early event.
• CDKN2A (p16/INK4A) loss short-circuits the Rb pathway.
• EGFR overexpression and RAS-MAPK activation drive proliferation and are the rational targets of cetuximab and panitumumab; PIK3CA, HRAS, KNSTRN and FAT1 accumulate with progression.
• Epithelial–mesenchymal transition — loss of E-cadherin, gain of vimentin, TWIST/SNAIL activation — marks the in-situ to invasive step and underlies desmoplastic and spindle-cell SCC.
• Perineural invasion is mediated by NGF/TrkA, NCAM and glial-derived neurotrophic factor signalling — the biology behind the high-risk phenotype. ^[1]

Field cancerization is the concept that changes management. A broad expanse of sun-damaged skin harbours multiple independent premalignant clones, each from a separate UV hit; AKs and in-situ SCCs are its visible markers, and invasive SCCs arise from within it. This is why field-directed therapy (5-FU, imiquimod, PDT) lowers the incidence of new invasive SCC across the whole field, not just at treated spots.^[7]

The premalignant precursors — the lesions you treat to prevent SCC

Actinic keratosis is the commonest precursor — intraepidermal keratinocyte dysplasia on sun-damaged skin; per-lesion progression to invasive SCC runs from about 0.025 percent up to 20 percent a year, higher in thick, hypertrophic lesions and in transplant recipients. SCC in situ (Bowen's disease) — full-thickness epidermal atypia — is the immediate precursor with much higher per-lesion risk and is treated definitively (excision, 5-FU, imiquimod, PDT, curettage plus cryotherapy).^[3][6]

Arsenical keratoses — punctate, yellow, keratotic, symmetric on palms and soles, with hyperpigmentation and Mee's lines — mark a high-risk patient after 10–40 years of latency. Chronic radiation dermatitis (atrophy, telangiectasia, poikiloderma, keratotic papules in a prior radiotherapy field) produces SCC after 20–40 years. Lichen sclerosus of the vulva carries a 4–5 percent lifetime risk of vulvar SCC; oral and vulval lichen planus carry similar risk — biopsy any nodule, erosion, hyperkeratosis or treatment-resistant lesion. Porokeratosis, erosive lichen planus, XP and albino skin, chronic stasis ulceration and dystrophic epidermolysis bullosa scars are all recognised precursors.^[1]

Clinical presentation — recognise the lesion and its danger signs

The classic lesion is a hyperkeratotic, scaling, crusted, indurated or ulcerated nodule or plaque on chronically sun-exposed skin — bald scalp, face, pinna, lower lip, dorsal hands, forearms — often tender or bleeding, arising within a field of actinic damage. In situ, AK is a rough scaly macule and Bowen's is a fixed, sharply demarcated scaly red patch.^[2][4]

High-risk clinical clues: size 2 cm or more, rapid growth, bleeding, fixation to deeper tissue, recurrence after treatment. Perineural disease announces itself with pain, numbness, tingling or motor weakness in a cranial-nerve distribution — a high-risk feature demanding MRI. Sites examiners test: the lower lip, pinna or ear, genital and perianal skin, the periungual or subungual region, within a burn scar (Marjolin), and in a transplant patient (multiple, fast-growing).^[1][6]

Morphological variants behave differently — name them because management diverges:^[3]

• Keratoacanthoma — a rapidly growing (weeks), symmetric, crateriform nodule with a central keratin plug; most dermatopathologists now treat it as a well-differentiated SCC variant. Excise it.
• Verrucous carcinoma — warty, exophytic, slow, locally destructive, rarely metastasising; sole (epithelioma cuniculatum), genitalia (giant condyloma of Buschke–Löwenstein), oral cavity, periungual. Radiotherapy is contraindicated — anaplastic transformation is well documented.
• Desmoplastic SCC — infiltrative, scar-like, ill-defined, sclerotic, head and neck; high recurrence and perineural invasion.
• Spindle-cell SCC — atypical spindles in a sun-damaged field; cytokeratins and p63 confirm epithelial origin and exclude atypical fibroxanthoma.
• Acantholytic (adenoid/pseudoglandular) SCC — pseudoglandular spaces; behaves as conventional.
• Marjolin ulcer — SCC in a burn scar, osteomyelitis sinus, venous ulcer or chronic wound, usually after decades; aggressive, high metastatic potential.
• Scar and radiation SCC — broader categories arising in post-traumatic or vaccination scars, or in chronic radiation dermatitis decades after irradiation. ^[1]

The mimics — and the discriminator that separates each

The discriminator line: a hyperkeratotic, indurated, tender or bleeding nodule on sun-damaged skin is SCC until histology says otherwise — biopsy the dermal component, do not freeze it blind.^[1]

Dermoscopy — the vessels tell you how deep the trouble is

Dermoscopy reads the spectrum along with the vessels. AK shows a pink-red "strawberry" pseudonetwork with surface scale and small white circles. Bowen's disease shows glomerular (coiled) vessels with milky-red areas and scale. Invasive SCC shows polymorphous vessels — hairpin, dotted and linear-irregular together — with central yellow-white keratin or ulceration and white structureless areas. Vascular polymorphism is the red flag for invasion.^[3]

Histopathology — the report that sets staging and risk

The histology report determines staging and management. Read it for these elements:^[2][3]

• Differentiation (well, moderate, poor) — poor differentiation is a high-risk feature.
• Invasion depth in mm — over 6 mm is a high-risk threshold.
• Perineural invasion, especially named nerves 0.1 mm calibre or more.
• Lymphovascular invasion, desmoplastic stromal reaction, subtype, and margins (involved, close, positive).
• Biopsy (shave, punch or incisional into dermis) suffices for diagnosis; small lesions may be excisional. ^[1]

High-risk features and staging — the list that picks Mohs

The high-risk feature set is the cornerstone of SCC management — it decides Mohs, margins, imaging and surveillance. Eight features, one mnemonic:^[1]

^[1]

The features in plain list (NCCN and Brigham agree): diameter 2 cm or more (1 cm or more on the mask area); invasion depth over 6 mm or Clark V; perineural invasion of a named nerve 0.1 mm calibre or more; poor differentiation; high-risk site (ear, non-glabrous lip, scalp, temple, mask area of face); immunosuppression; prior radiotherapy; recurrence; rapid growth; lymphovascular invasion; desmoplastic subtype.^[1][6]

Staging — two systems, prefer Brigham for prognosis. AJCC 8th edition T: T1 is up to 2 high-risk features, T2 is 2 or more (excluding bone), T3 is not used for cutaneous, T4 is bone invasion. Brigham (BWH) is more prognostic: T1 = 0 risk factors, T2 = 1, T3 = 2 risk factors, T4 = bone invasion (all high-risk). Regional nodes — N1 a single ipsilateral node up to 3 cm, N2 a single 3–6 cm or multiple ipsilateral up to 6 cm, N3 over 6 cm or bilateral. Distant metastasis goes to lung first, then bone, liver and brain.^[1]

The bedside round — examine the field, not just the lesion

• Examine the lesion and the entire sun-exposed field (scalp, face, ears, lips, hands) and assess high-risk features at the bedside.^[6]
• Palpate regional nodes — parotid for face and scalp lesions; cervical, axillary, inguinal basins.
• Cranial nerve examination for any face or scalp lesion — perineural disease is missed by eyes that look only at the skin.
• Examine the oral mucosa and lips. ^[1]

Investigations — biopsy to confirm, image when high-risk

• Biopsy the dermal component (shave, punch or incisional) for diagnosis; small lesions may be excisional.^[1]
• Imaging is reserved for high-risk tumours and suspected invasion: MRI for perineural, bone or skull-base disease; CT for nodal or parotid disease; PET-CT for advanced or metastatic staging.
• Node ultrasound with FNA for clinically suspicious nodes.
• Sentinel lymph node biopsy is not standard for cutaneous SCC — limited prognostic and therapeutic evidence. NCCN, EADO and BAD advise imaging surveillance (ultrasound with or without CT/MRI) for high-risk tumours and therapeutic lymph node dissection for clinically positive disease; SLNB only in selected high-risk patients within a multidisciplinary discussion.
• Advanced-disease staging: contrast CT chest/abdomen/pelvis (lung is the commonest first metastasis), brain MRI if neurological symptoms, baseline FBC, LFTs, renal function and LDH. ^[1]

Surgery — first-line, with margins set by risk

Surgery is first-line for invasive SCC, and the margins track the risk.^[2][3]

• Excision margins: 4-6 mm for low-risk tumours (to subcutaneous fat); 6 mm up to 10 mm for high-risk tumours.
• Mohs micrographic surgery is preferred for high-risk tumours, recurrent SCC, the mask area of the face and other critical or cosmetic sites (eyelid, nose, lip, ear, genital, perianal, digit), ill-defined margins, tumours over 2 cm, and immunosuppressed patients — highest cure rate with maximal tissue conservation.^[2]
• Curettage and electrocautery only for small, low-risk, non-critical-site lesions in low-risk patients. ^[1]

In situ disease and the field — treat the field to prevent the next SCC

• SCC in situ (Bowen's disease): topical 5-FU or imiquimod, photodynamic therapy (PDT), cryotherapy, curettage, or excision for refractory or large lesions.^[3]
• Field cancerization and multiple AK: field-directed 5-FU, imiquimod or PDT, and chemical peel — these reduce the burden of premalignant clones and lower the incidence of new invasive SCC across the field.^[7]

Radiotherapy — adjuvant for high-risk, never for verrucous

• Primary radiotherapy for unresectable tumours or patients unfit for surgery — a lower cure rate than surgery, reserved for palliation, the very elderly, or surgically unfavourable sites.^[1]
• Adjuvant radiotherapy after excision of high-risk tumours — perineural (named nerve), bone invasion, close or involved margins, positive nodes, recurrent disease.
• Verrucous SCC is a contraindication to radiotherapy — anaplastic transformation is well documented. This is a classic exam trap.
• Standard regimens: orthovoltage or megavoltage photons, 50–70 Gy in 2–3 Gy fractions over 3–6 weeks; electron boost for superficial tumours; brachytherapy for selected sites. ^[1]

Nodal and advanced disease — parotidectomy for nodes, cemiplimab for the rest

• Clinically positive nodes (face or scalp draining to parotid and cervical chains): parotidectomy plus neck dissection plus adjuvant radiotherapy.^[1]
• Advanced, metastatic or unresectable SCC: cemiplimab (anti-PD-1 — the first agent approved for advanced cutaneous SCC; FDA 2018, EMA 2019; objective response 47.2% across EMPOWER-CSCC-1 groups 1-3 at long-term follow-up); pembrolizumab (KEYNOTE-629: response 35.2% in recurrent/metastatic and 50.0% in locally advanced disease); EGFR inhibitor cetuximab for PD-1-refractory disease; radiotherapy for local control.^[8][9][3]
• Hedgehog inhibitors (vismodegib, sonidegib) are for BCC, not pure SCC — the dominant molecular target in SCC is PD-1, with EGFR second-line. They figure only in rare combined or basosquamous tumours.^[1]

Systemic therapy doses the examiner expects you to know

Specific doses and regimens — name the drug, the dose and the trial:^[2][3]

• Cemiplimab (anti-PD-1; the first systemic agent approved for advanced cutaneous SCC, FDA 2018, EMA 2019): 350 mg IV over 30 minutes every 3 weeks until progression or unacceptable toxicity. In EMPOWER-CSCC-1, the objective response rate across locally advanced and metastatic disease was 47.2% at 42.5 months of follow-up, with an estimated 12-month duration of response of 88.3%; in metastatic disease, fixed-dose 350 mg every 3 weeks gave an objective response rate of 41.1%.^[8][11] In locally advanced disease, 3 mg/kg every 2 weeks produced an objective response in 44% (complete response 13%).^[11] Baseline work-up: hepatitis B/C and HIV serology, latent TB screening, thyroid function, FBC, LFTs, renal function, cortisol.^[3] Immune-related adverse events (dermatitis, colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis) are managed with corticosteroids per ESMO guidance; infliximab for steroid-refractory colitis.^[3]
• Pembrolizumab (anti-PD-1): 200 mg IV every 3 weeks for up to 35 cycles. In KEYNOTE-629 the objective response rate was 50.0% in the locally advanced cohort (complete response 16.7%) and 35.2% in the recurrent/metastatic cohort (complete response 10.5%); grade 3-5 treatment-related events occurred in 11.9%.^[9] Same irAE monitoring as cemiplimab.^[3]
• Cetuximab (anti-EGFR chimeric IgG1 — second-line after PD-1 failure or contraindication): in a 20-patient study of inoperable advanced disease, cetuximab alone or with radiotherapy or carboplatin gave an overall response rate of 47% and disease control of 78%; monotherapy responses were seen in a third of patients.^[15] Premedicate against infusion reactions; acneiform rash is the hallmark toxicity; monitor magnesium for hypomagnesaemia.^[3]
• Panitumumab (fully human anti-EGFR IgG2): 6 mg/kg IV every 2 weeks. In a phase II study of incurable cutaneous SCC, the best response rate was 31% (two complete, three partial responses) with median progression-free survival of 8 months.^[14]
• Hedgehog pathway inhibitors (Smoothened inhibitors — for BCC, not cutaneous SCC): vismodegib 150 mg orally once daily gave an overall response rate of 42.9% in locally advanced and 30.3% in metastatic BCC in ERIVANCE BCC; sonidegib 200 mg orally once daily gave 61% response in locally advanced BCC in the BOLT trial.^[1][3] Class toxicities: muscle spasm, alopecia, dysgeusia, weight loss, teratogenicity. Cutaneous SCC has no established hedgehog-inhibitor signal; PD-1 is first target, EGFR second.^[3]
• Platinum chemotherapy (PD-1-refractory disease or rapid cytoreduction): cisplatin-based regimens or carboplatin; responses are modest and short-lived.^[3] Cemiplimab showed superior survival outcomes versus platinum-based chemotherapy in indirect comparisons.^[3]
• Adjuvant anti-PD-1 after surgery in high-risk disease: in the phase 3 C-POST trial, adjuvant cemiplimab 350 mg IV every 3 weeks for 12 weeks then 700 mg every 6 weeks, to a maximum of 48 weeks, cut recurrence or death versus placebo (HR 0.32); estimated disease-free survival at 24 months was 87.1% versus 64.1%.^[10]
• Dose modifications and toxicity thresholds: hold anti-PD-1 therapy for grade 3 or worse immune-related adverse events until resolution to grade 1 or baseline. Manage immune-related adverse events with systemic corticosteroids first; use infliximab for steroid-refractory colitis.^[3] Permanently discontinue for life-threatening events. Stop cetuximab for grade 3-4 infusion reactions.^[3]

Special populations — the transplant patient is the one who changes everything

• Solid-organ transplant recipients and the immunosuppressed: SCC is commoner, more aggressive, multiple, and a leading cause of long-term post-transplant death. One in twenty recipients develops a highly morbid or fatal cutaneous carcinoma.^[6][12] The pillars are reduce immunosuppression where possible, consider mTOR inhibitor (sirolimus) conversion, intensive dermatology surveillance, aggressive treatment of high-risk tumours, and field therapy.^[1] In the TUMORAPA trial, conversion to sirolimus cut new squamous cell carcinomas at 2 years (22% vs 39%; relative risk 0.56); the benefit held at 5 years.^[12] A second randomised trial found lower NMSC rates with conversion (1.31 vs 2.48 lesions per patient-year).^[12] Acitretin chemoprevention is used in selected high-risk recipients: acitretin 30 mg daily for 6 months reduced new squamous cell carcinomas versus placebo (11% vs 47% of patients).^[13] Monitor for hyperlipidaemia, hepatotoxicity and teratogenicity.^[3]
• Chronic wound or burn scar (Marjolin ulcer): treat as high-risk — wide excision with or without radiotherapy; high metastatic potential.
• Lichen sclerosus and lichen planus: chronic inflammation predisposes; biopsy any nodule or non-healing erosion. Vulvar SCC in lichen sclerosus is managed by gynaecological oncology.
• Lip SCC: higher metastatic potential; nodal surveillance and specialist lip reconstruction.
• HIV/AIDS: more aggressive SCC; coordinate antiretroviral optimisation and apply high-risk thresholds.
• Xeroderma pigmentosum: extreme UV avoidance from birth, oral isotretinoin or acitretin chemoprevention, aggressive excision, physician skin examination every 3-12 months.^[3]
• Chronic lymphocytic leukaemia: in a Danish nationwide cohort, 10-year risk of squamous cell carcinoma was 4.7% versus 1.4% in matched controls, and skin-cancer-specific metastasis and death were both increased; coordinate with haematology.^[1]

Prognosis and surveillance — excellent when low-risk, lifelong for everyone

• Low-risk tumours have an excellent prognosis — surgical cure over 90–95 percent.^[2][6]
• Metastasis runs about 3–5 percent overall but climbs steeply with high-risk features — perineural invasion, depth over 6 mm, immunosuppression, lip or ear site, recurrence, poor differentiation. Metastatic cutaneous SCC carries a poor prognosis.
• Cutaneous SCC causes substantial mortality despite a low per-tumour rate because of its sheer volume.
• Surveillance is lifelong and risk-stratified: high-risk and immunosuppressed patients every 3–6 months with full skin and node examination; sun protection and field therapy to reduce new primaries. ^[7]

Evidence, guidelines and the regional differences

Guidelines (NCCN for North America, EADO/EORTC for Europe, BAD for the UK; Cancer Council Australia for the high-incidence sun-belt) agree on the framework; the Brigham versus AJCC 8th staging debate continues, with Brigham stratifying prognosis more granularly. The transforming development of the last decade is cemiplimab and anti-PD-1 for advanced SCC; neoadjuvant and perioperative immunotherapy and gene-expression profiling are emerging.^[1][6]

Prevention — sun, field, and the transplant clinic

• Sun protection — shade, clothing, broad-spectrum SPF 30-plus; avoid indoor tanning.^[5]
• Field therapy of actinic damage and treatment of AKs to lower new invasive SCC incidence.
• Transplant and immunosuppressed surveillance clinics; sirolimus conversion where appropriate; acitretin chemoprevention in selected high-risk recipients.^[1]
• Tobacco cessation (lip SCC); HPV vaccination (anogenital and oropharyngeal SCC prevention). ^[5]

The mantra

The mantra: biopsy every non-healing nodule on sun-damaged skin, split it low-risk from high-risk with BIG-CRIMP, and never irradiate a verrucous SCC — cemiplimab is what you reach for when surgery has done all it can.^[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the builder's scalp (answer)ShowHide

A 74-year-old retired builder has a crusted, bleeding, hyperkeratotic nodule on his bald scalp, surrounded by gritty actinic keratoses. What is it, what must you examine, and what is the first step? Model: This is invasive cutaneous SCC on a field of actinic damage. Examine the whole sun-exposed field and palpate the regional nodes (parotid and cervical for a scalp lesion), and check the cranial nerves for perineural disease. The first step is a biopsy of the dermal component — not blind cryotherapy — to confirm invasion and read differentiation, depth, perineural and lymphovascular invasion. Then risk-stratify with BIG-CRIMP to choose between 4-6 mm excision (low-risk) and Mohs (high-risk).^[1]

Stem 2 — numbness in a facial tumour (answer)ShowHide

An 80-year-old has an SCC on his cheek. Three months in, he reports numbness and tingling over the maxillary division of the trigeminal nerve. What has happened, what investigation is mandatory, and how does it change management? Model: This is perineural invasion — a high-risk feature (the C in BIG-CRIMP) presenting with pain, numbness, tingling or motor weakness in a cranial-nerve distribution. MRI of the face and skull base is mandatory to map the nerve. Management shifts to Mohs micrographic surgery with adjuvant radiotherapy within a multidisciplinary team — perineural disease of a named nerve (0.1 mm calibre or more) drives recurrence and nodal spread.^[1]

Stem 3 — multiple fast-growing tumours in a transplant recipient (answer)ShowHide

A 55-year-old renal transplant recipient, eight years out, presents with four new hyperkeratotic nodules on his scalp and hands in six months. What is the underlying problem, what two therapeutic levers change his immunosuppression, and what is the surveillance plan? Model: This is the transplant SCC phenotype — the SCC:BCC ratio inverts to about 4:1, and tumours are multiple, aggressive and early. The two levers are reduce the overall immunosuppressive load where graft function allows, and consider conversion to an mTOR inhibitor (sirolimus), which lowered new squamous cell carcinomas at 2 years (22% vs 39%; relative risk 0.56) and reduced NMSC rates at 5 years.^[12] Add acitretin chemoprevention in selected patients (30 mg daily halved new squamous cell carcinomas over 6 months versus placebo) and institute intensive dermatology surveillance every 3–6 months with field therapy of actinic damage. Each tumour is risk-stratified and treated on its own merits (Mohs for high-risk sites).^[1][13]

^[1]

References15ShowHide

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2. [2]Wysong A. Squamous-Cell Carcinoma of the Skin N Engl J Med, 2023.PMID 37314707
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13. [13]Bavinck JN, Tieben LM, van der Woude FJ. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study J Clin Oncol, 1995.PMID 7636533
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