12-phase flow (12)

1. 1FRAME
   Frame cSCC as the second most common cutaneous malignancy and the leading cause of NMSC mortality — most cures are achieved by simple local therapy, but a definable high-risk subset (Brigham T2b/T3, organ-transplant, PNI, deep invasion) drives meaningful nodal and death risk and requires Mohs / margin-assessed excision ± adjuvant RT and frequently checkpoint immunotherapy for advanced disease. The dermatology engine owns recognition / biopsy / risk stratification / definitive local therapy / cemiplimab-pembrolizumab systemic ladder; routes only bona-fide distant metastatic / unresectable head-and-neck disease to multidisciplinary care.
   advance: derm-owned scope set; sibling routes (BCC, AK-NMSC, melanoma) noted
2. 2ENTRY
   Recognise a persistent hyperkeratotic firm/tender plaque or nodule, a rapidly growing keratoacanthoma-like nodule, a non-healing ulcer / Marjolin scar, an SCC-in-situ erythematous scaly patch (Bowen), or a transplant / chronic-immunosuppression surveillance entry. Capture morphology + site up front.
   inputs: lesion_morphology_and_anatomic_site
   actions: workup.chronic_pruritus
   advance: entry trigger recognised; morphology + site recorded
3. 3CONTEXT
   Build the recognition context: UV burden + cumulative actinic field; total-body skin exam for synchronous AK + BCC + SCC + melanoma; immunosuppression / transplant / CLL / HIV / xeroderma pigmentosum / epidermodysplasia status; prior NMSC count (drives chemoprevention threshold); Marjolin / scar / chronic-wound history; family history including Gorlin (PTCH1) for the BCC differential.
   inputs: immunosuppression_or_transplant_status
   actions: workup.chronic_pruritus
   advance: total-body skin exam done; immunosuppression context established; field context for surrounding AK / NMSC routed
4. 4RED_FLAGS
   Perineural invasion symptoms (named-nerve pain, paraesthesia, motor weakness, facial palsy) -> urgent MRI + multidisciplinary care. Palpable regional lymph nodes -> imaging + FNAC/core biopsy. Bona-fide distant metastasis (lung, bone, liver) is rare overall (~2-5%) but high in T2b/T3 disease and devastating in transplant recipients. Severe checkpoint-inhibitor irAE in patients on routed cemiplimab/pembrolizumab is an emergency.
   inputs: perineural_or_motor_sensory_symptoms, regional_node_examination
   actions: panel.cbc, panel.inflammation
   advance: PNI, nodal, metastatic, irAE flags screened and routed if positive
5. 5INITIAL_WORKUP
   DIAGNOSTIC BIOPSY: shave or punch biopsy of the most representative area, sampling to dermis for adequate depth; full-thickness biopsy is preferred when the depth of invasion will materially alter management (eg suspected Marjolin / desmoplastic cSCC). Histology must report subtype, differentiation, depth of invasion / thickness, perineural invasion (with named nerve if visible), lymphovascular invasion, and margin status when an excision specimen. Baseline labs (CBC, LFT, creatinine) only when systemic therapy or staging imaging is anticipated.
   inputs: lesion_morphology_and_anatomic_site, differentiation_grade_on_biopsy, cbc_with_differential, lft
   actions: panel.cbc, panel.lft
   advance: biopsy obtained with full histopathologic reporting; baseline labs drawn if systemic therapy anticipated
6. 6BRANCHING_WORKUP
   Histopathology + clinical risk drive the branch: low-risk -> excision / ED&C / topical for in situ. High-risk -> Mohs OR margin-assessed excision + adjuvant RT consideration; CT/MRI for PNI / orbital / bone invasion; regional-node imaging (US or CT) if any clinical suspicion or NCCN very-high-risk. Locally advanced / unresectable / metastatic -> cross-sectional staging (CT chest-abdomen-pelvis + CT/MRI head-and-neck) + systemic ladder (cemiplimab first-line, pembrolizumab alternative). SLNB is controversial in high-risk cSCC and is NOT routine.
   inputs: tumor_size_and_borders, depth_of_invasion_or_clinical_thickness, recurrence_status_and_prior_rt, staging_imaging_for_high_risk_or_advanced
   actions: panel.inflammation
   advance: risk tier (low / high / locally advanced / metastatic) assigned; appropriate imaging done; treatment route selected
7. 7DIFFERENTIAL
   Terminal differential with named pivots: cSCC vs actinic keratosis (rough hyperkeratotic macule WITHOUT firm/tender base — route derm.actinic-keratosis-nmsc.core.v1; cumulative AK->SCC risk) vs SCC in situ / Bowen (well-demarcated erythematous scaly patch, no invasion pivot) vs basal cell carcinoma (pearly translucent + arborising vessels + rolled border — route derm.basal-cell-carcinoma.core.v1; basosquamous is the hybrid) vs keratoacanthoma (rapidly growing crateriform nodule that may spontaneously regress — but a subset are well-differentiated SCC; treat as cSCC unless certain) vs hypertrophic AK (intermediate; low threshold for biopsy) vs verrucous carcinoma (slow-growing exophytic cauliflower-like; underdiagnosed) vs amelanotic melanoma (asymmetric / rapidly growing pink-red lesion — route derm.melanoma.core.v1) vs Merkel-cell carcinoma (rapidly growing red-purple nodule in elderly / immunosuppressed — high-yield biopsy + MDT). Marjolin in a chronic scar / burn / wound is cSCC until proven otherwise.
   advance: best diagnosis selected; melanoma / Merkel branch resolved by biopsy if any doubt
8. 8RISK_STRATIFICATION
   NCCN cSCC 2025 + Brigham T-staging (schema-blocked as a TS calculator — captured narratively). LOW-RISK = trunk/extremity <2 cm, well-defined, primary, immunocompetent, well/moderately differentiated, no PNI, no aggressive features. HIGH-RISK = size H-zone any / M-zone ≥1 cm / L-zone ≥2 cm, ill-defined borders, recurrent, immunosuppressed, prior RT site, scar/chronic-ulcer origin (Marjolin), poorly differentiated, perineural invasion ≥0.1 mm, invasion beyond subcutaneous fat OR thickness >6 mm, lymphovascular invasion, desmoplastic subtype. VERY-HIGH-RISK (Brigham T2b/T3) = ≥2 of: diameter ≥2 cm, poor differentiation, PNI ≥0.1 mm, invasion beyond fat. Risk tier drives local therapy intensity, adjuvant RT decision, and need for nodal/distant staging.
   inputs: tumor_size_and_borders, depth_of_invasion_or_clinical_thickness, differentiation_grade_on_biopsy, recurrence_status_and_prior_rt
   advance: NCCN risk tier + Brigham stage assigned
9. 9TREATMENT
   RISK-DIRECTED LOCAL THERAPY (NCCN cSCC 2025). LOW-RISK: standard surgical excision 4-6 mm clinical margins (non-pharm) OR electrodesiccation-and-curettage (non-pharm, NOT terminal-hair-bearing). SCC IN SITU (Bowen): excision OR topical 5-fluorouracil 5% BID x 2-4 wk OR imiquimod 5% 5x/wk x 12-16 wk OR PDT. HIGH-RISK / VERY-HIGH-RISK: MOHS micrographic surgery (preferred) OR excision with intra-operative frozen-section complete-margin assessment; ADJUVANT RT for PNI of a named nerve, positive deep margin where re-excision unfeasible, extranodal extension, or maximally-resected very-high-risk disease. LOCALLY ADVANCED / UNRESECTABLE / METASTATIC: cemiplimab 350 mg IV q3wk first-line (EMPOWER-CSCC-1 PMID 29863979; ORR ~47%); pembrolizumab 200 mg IV q3wk as alternative (KEYNOTE-629 PMID 32673170 / 34293460; LA ORR 50.0%, R/M ORR 35.2%). CHEMOPREVENTION for high-risk (transplant recipients, multiple prior NMSC): nicotinamide 500 mg po BID (ONTRAC PMID 26488693). TRANSPLANT-RECIPIENT cSCC: coordinate with transplant team for immunosuppression reduction / mTOR-inhibitor switch (sirolimus / everolimus) for those with recurrent/multiple SCC.
   inputs: immunosuppression_or_transplant_status, creatinine_and_egfr
   advance: risk-appropriate local therapy chosen OR systemic ladder started for advanced disease; transplant-team coordination if applicable; chemoprevention discussed
10. 10DISPOSITION
    Almost entirely outpatient. Multidisciplinary tumour-board referral for: locally advanced / unresectable disease, PNI of named nerves, regional / distant metastasis, transplant recipients with high-risk disease, planned major reconstructive surgery, or any disease being considered for systemic immunotherapy. Radiation oncology for definitive RT (non-surgical candidate) or adjuvant RT. Transplant nephrology / hepatology for immunosuppression review. Head-and-neck surgical oncology for parotid / cervical nodal disease.
    inputs: perineural_or_motor_sensory_symptoms, regional_node_examination
    advance: disposition documented; MDT / radiation oncology / transplant team / head-and-neck referrals made as indicated
11. 11MONITORING
    Surveillance is intensified: total-body skin exam every 3-6 months for years 1-2 in high-risk patients, then every 6-12 months lifelong; 30-50% second-NMSC risk overall, much higher in transplant. On cemiplimab / pembrolizumab: routine irAE surveillance (skin, thyroid TSH every cycle, hepatitis LFT, colitis symptoms, pneumonitis cough/dyspnoea, hypophysitis, myocarditis with cTn / ECG as indicated). Adjuvant RT toxicity (mucositis, xerostomia for head-and-neck fields). Regional nodal exam at each follow-up for high-risk primaries.
    inputs: cbc_with_differential, lft
    actions: panel.cbc, panel.lft, panel.inflammation
    advance: intensified surveillance + agent-specific monitoring schedule set
12. 12FOLLOWUP
    Lifelong derm continuity with emphasis on photoprotection (broad-spectrum SPF ≥30 + sun-protective clothing + behavioural avoidance), structured skin self-examination + regional-node self-check education, AK / field-therapy maintenance (route derm.actinic-keratosis-nmsc.core.v1 for ongoing field treatment), and nicotinamide chemoprevention for transplant recipients / multiple prior NMSC (ONTRAC PMID 26488693). Organ-transplant recipients receive intensified surveillance + transplant-team coordination on immunosuppression. Recurrence at the prior site -> re-biopsy + escalate (Mohs re-excision, adjuvant RT, or systemic therapy if unresectable).
    inputs: immunosuppression_or_transplant_status, recurrence_status_and_prior_rt
    actions: workup.chronic_pruritus
    advance: photoprotection + self-exam + field-therapy + chemoprevention + intensified surveillance documented