Cancer risk in CLL

Cutaneous SCC — relative risk ~5–10× general population (cohort-dependent); aggressive behaviour with elevated metastasis (15–25%) and disease-specific mortality.
Cutaneous BCC — relative risk ~2×; multiple synchronous and metachronous lesions.
Cutaneous melanoma — relative risk ~2–3.5× (cohort-dependent); stage-for-stage worse outcomes.
Merkel cell carcinoma — relative risk ~10–30×; CLL is the strongest single-condition risk factor for MCC.
Cutaneous T-cell lymphoma — increased risk of mycosis fungoides / Sézary in CLL is debated.
Kaposi sarcoma — modestly increased.
Other cancers — increased risk of head-and-neck SCC, lung carcinoma, colorectal carcinoma, breast carcinoma, sarcoma.
Mechanism — chronic immune dysregulation of CLL (hypogammaglobulinaemia, T-cell exhaustion, NK-cell impairment) reducing immune surveillance against UV-driven keratinocyte cancers and oncogenic viral infections.
Risk amplified by:
- CLL therapies — purine analogues (fludarabine), monoclonal antibodies (rituximab, obinutuzumab), BTK inhibitors (ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax) — all worsen infection / second-cancer risk.
- Smoking, UV exposure, fair skin.
- Voriconazole exposure if used for fungal prophylaxis — note the voriconazole-cSCC association is most strongly demonstrated in lung-transplant recipients; the CLL evidence is weaker and antifungal switching should be a multidisciplinary decision.

Aggressive behaviour

Cutaneous cancers in CLL behave more aggressively:
- Multiple synchronous and metachronous lesions.
- Faster growth.
- Higher recurrence rate after standard treatment.
- Higher metastatic risk.
- Worse stage-for-stage outcomes.
This justifies more aggressive primary surgical management, lower threshold for sentinel lymph node biopsy and adjuvant radiotherapy, and earlier consideration of immune checkpoint inhibitors for advanced disease.
"Leukaemia cutis" — direct cutaneous infiltration by CLL cells; presents as red-violaceous papules / plaques; may be the presenting feature; biopsy with flow cytometry confirms.
"Insect bite-like reactions" of CLL — exaggerated reactions to insect bites; persistent itchy bullous papules; histologically eosinophil-rich infiltrates; not directly malignant but characteristic.

Paraneoplastic pemphigus — strong association; CLL is one of the principal underlying malignancies; severe stomatitis + polymorphic skin eruption + bronchiolitis obliterans — see monograph.
Sweet syndrome — paraneoplastic association; tender erythematous plaques + fever + neutrophilia — see monograph.
Pyoderma gangrenosum — paraneoplastic association.
Acquired ichthyosis — see monograph.
Acquired angio-oedema from acquired C1 esterase inhibitor deficiency.

Multidisciplinary care — haematology / CLL specialist, dermatology, plastic surgery, oncology; lifelong.
Skin surveillance:
- Annual full skin examination from CLL diagnosis (6-monthly if previous skin cancer or Merkel-spectrum risk factors).
- Patient self-examination education.
- Lower threshold for biopsy of any new or changing lesion.
Photoprotection — broad-spectrum SPF 50+ daily, sun-protective clothing.
Smoking cessation.
HPV vaccination if not previously received.
Skin cancer treatment:
- Excisional surgery is the cornerstone; aggressive primary surgery with consideration of wider margins and SLNB.
- Mohs micrographic surgery for facial / functionally important sites.
- Adjuvant radiotherapy for incomplete margins, multiple positive nodes or perineural invasion.
- Cemiplimab (NICE TA802) for advanced / metastatic cSCC — caution but generally well tolerated in CLL; multidisciplinary discussion.
- Pembrolizumab for advanced melanoma; avelumab for advanced MCC (NICE TA691).
- Field treatment with 5-FU, imiquimod, PDT for AKs (use cautiously in CLL given immune dysregulation; topical responses may be less robust).
Optimise CLL control — improving CLL disease activity may reduce immune dysregulation and second-cancer risk; coordinate with haematology MDT.