Cryotherapy

Meet the patient

A GP rings at 5pm. "I've got a 60-year-old with a 'wart' on his back — can I just freeze it off?" The patient is dark-skinned, the lesion is new, darkly and irregularly pigmented, and nobody has dermoscoped it. The answer is no, and the reason is the whole topic in one line: cryotherapy destroys tissue, so you lose the histology. A pigmented lesion in an older adult is melanoma until dermoscopy and biopsy prove otherwise.[1]

Carry two questions through everything that follows. Is the diagnosis secure enough to destroy without histology? And is this the right lesion, site, and patient for a freeze that will leave a permanent lighter macule? Get both right and cryotherapy is safe, quick, and cheap; get either wrong and the file ends up in a courtroom.[9]

The mantra, up front

Confirm the diagnosis before you destroy it — cryotherapy forfeits the specimen.[1]

Everything below defends that single line. The cold is cheap, fast, and forgiving of everything except a wrong diagnosis.[1]

What the word means — and why the ice ball is visible

Cryo comes from the Greek kryos, "cold" — the same root that names the cryoglobulins you must ask about before picking up the gun. The clinically useful fact is that the ice ball is the lesion's execution made visible: the white frozen disc you watch at the bedside is, in cross-section, an isotherm map, and the rim you grow it to is the lethal isotherm of approximately -20 to -30 C. Inside that rim the tissue dies; outside it survives. Your whole technique is the controlled growth of that disc to a measured margin.[1]

Liquid nitrogen boils at -196 C — the coldest practical cryogen, and the only one cold enough for malignancy. Nitrous oxide (-89 C) and carbon dioxide snow (-78.5 C) still turn up in dental surgeries but cannot reach the destructive depth or cooling rate the skin demands. When an examiner says "cryotherapy" in dermatology, they mean liquid nitrogen by spray, cotton tip, or contact probe.[1]

CRYO — the four things that define the tool

[1]

Cost and speed are why cryotherapy outlives flashier technology; recurrence and the missing specimen are why it has boundaries. The Y is dosimetry — the rim you watch at the bedside. The O is the two prices you pay every time, and the second one never fades.[9]

The four deaths — a cascade, not one event

Freezing does not kill by cold alone. Four mechanisms converge, each on its own clock, and the candidate who names all four in order answers most of the viva. The cascade runs from outside the cell inward, then out through the blood supply, then late by suicide.[1]

Mechanism 1 — extracellular ice and the solute-effect. Ice forms first in the extracellular fluid, which is more dilute than cytoplasm. As the ice grows it excludes solutes, so the remaining unfrozen fluid turns sharply hyperosmolar and pulls water out of the cell. The cell shrinks, its proteins denature, and its intracellular salts climb to toxic levels — the solute-effect. Many cells die of this biochemical injury before any ice ever forms inside them.[1]

Mechanism 2 — intracellular ice and membrane rupture. Cool fast enough and the cytoplasm supercools, then nucleates ice inside the cell. This is the single most lethal mechanism in cryosurgery: crystals shred the plasma membrane, rupture organelles, and fracture the cytoskeleton. It is why the rate of cooling matters, and why the open spray — which cools fast — is more destructive than the cotton bud for the same nominal freeze time.[1]

Mechanism 3 — vascular stasis and ischaemia. Cold injures the dermal microvasculature. Endothelium swells, capillaries leak, then thrombose, and the target tissue is secondarily infarcted over the hours after treatment. This mechanism widens the kill-zone beyond the directly frozen cells and is why a pyogenic granuloma, once thrombosed, can be conquered by cold.[1]

Mechanism 4 — apoptosis at the periphery. At the rim of the ice ball the temperature is sub-lethal but still cold. Cells here do not rupture; they undergo programmed cell death over the following hours, extending the margin of necrosis beyond what the visible ice ball promised. This is why the histological zone of death is larger than the white disc you watched at the bedside.[1]

The thaw matters as much as the freeze

Why a slow thaw magnifies the kill — and why two cycles beat one

During a slow, passive thaw, the tiny ice crystals that formed in the rapid freeze coalesce and grow (recrystallisation), gouging the membranes afresh and letting the solute-effect grind on longer. You never apply heat or pressure to speed thawing — you wait for the tissue to return fully to body temperature. Each freeze-thaw cycle widens the zone of complete necrosis, because cells that survived the first freeze — especially at the deep margin — are caught by the second. That is why premalignant and malignant lesions always receive two cycles.[2]

Why melanocytes die first — the signature complication

Melanocytes are markedly more cold-sensitive than keratinocytes. They are destroyed at warmer temperatures than the cells around them, so any freeze intense enough to treat the lesion is intense enough to wipe out the melanocyte population at the site. The result is permanent hypopigmentation — the single most important long-term adverse effect of cryotherapy, and the dominant consideration whenever the patient is dark-skinned.[9]

[9]

The discipline is simple in the chair and harder at 5pm in a full clinic: photograph, counsel, and freeze only what you are certain of.[9]

Three ways to deliver the cold

The delivery technique is chosen for lesion size, thickness, site, and the precision required — each method trades control against depth.[1]

[1]

A fourth, cryopeeling, sprays a fine LN2 mist over a whole cosmetic unit (usually the face) for widespread actinic damage or, in selected hands, inflammatory acne. It is an expert technique, rarely examined beyond its name.[1]

The dosimetry ladder — match the freeze to the lesion

Freeze time and cycle count are not arbitrary. They are calibrated to lesion thickness, biology, and recurrence risk. Read the table as a dosing chart, not a menu.[1]

[1]

The wart ladder — the longest ladder in dermatology

Warts are the commonest indication and the one with the most rungs. Patient-applied salicylic acid paint or plaster (12-26%, soaked and filed daily for up to 12 weeks) is genuinely first-line and at least as effective as cryotherapy head-to-head. Cryotherapy is the office option, every 3-4 weeks for up to three or four sessions. For thick plantar warts, pare the callus before freezing and combine with salicylic acid between visits. Needling (repeated puncture under local anaesthetic to provoke immunity) and intralesional bleomycin sit further up the ladder for the refractory few.[6]

The VRAIE trial (Chanal and colleagues, 2025) randomised previously-treated plantar warts to salicylic acid, liquid nitrogen, 5-fluorouracil, or imiquimod — and found no single agent clearly superior. Plantar warts are stubborn, and the choice is patient-tailored, not algorithmic.[7]

The actinic keratosis ladder

For discrete AK, lesion-directed cryotherapy is first-line: a single 5-8 second freeze with a 2 mm halo usually suffices. For field cancerisation with many lesions, treating them one by one is inefficient — field therapy with topical 5-fluorouracil, imiquimod, or photodynamic therapy is preferred, with cryotherapy reserved for the few thick lesions field treatment leaves behind. The Worley (2023) systematic review and the Dianzani (2020) review agree: cryotherapy, field therapy, and PDT have comparable moderate efficacy per lesion, but field therapy wins when lesion count is high.[5][4]

The superficial BCC ladder — narrow ground

Excision with margin control is first-line for BCC of every subtype. Cryotherapy has a narrow, defined role: carefully selected low-risk superficial BCC on the trunk or limbs, typically under 1 cm, where the patient is unsuitable for or declines surgery. The protocol is aggressive — 30 seconds per cycle, two cycles, a 5 mm halo — with mandatory review at 3-6 months and a low threshold to biopsy anything persistent. The European consensus guidelines (Peris and colleagues, 2019) place cryotherapy among several nonsurgical options for low-risk superficial BCC but stress that surgery is first-line and cryotherapy is wrong for nodular, morpheaform, or facial lesions.[8]

Escalate — always by biopsy, never by re-freezing — when a lesion fails to clear after 3-4 sessions, recurs after apparent clearance, or shows induration, rapid growth, or ulceration in a treated BCC or Bowen. The response is histology, not more cold.[1]

The decision that protects patients — what never gets frozen

Cryotherapy is a decision about what does NOT need histology. The table frames it the way an examiner does: first-line, acceptable-in-selected, prefer-excision, and never.[1]

[1]

The classic trap

The classic trap: a registrar freezes a "seborrhoeic keratosis" on a sun-damaged back that turns out to be melanoma. The specimen is now vapour, the margins are unknowable, the staging is delayed, and the patient's prognosis has worsened for the want of a punch biopsy. The discipline that prevents it is one rule: any pigmented lesion that is irregular, changing, darkly and variably pigmented, or bleeding is melanoma until dermoscopy and biopsy prove otherwise — and melanoma is never a cryotherapy indication.[1]

When NOT to freeze — the never list

[3]

Absolute contraindications are few but absolute: any lesion needing histology (suspected melanoma, undiagnosed pigmented lesion, lesion of uncertain nature) and any serious cold-intolerance disorder with systemic risk. Relative contraindications are the practical balance: darker phototypes at visible sites; peripheral and digital sites in Raynaud or compromised circulation; thin atrophic elderly skin; immunosuppression (poor healing, infection, refractory lesions); and lesions over cartilage. Pregnancy is not a contraindication — there is no systemic absorption of significance.[3]

The complication clock — immediate, early, late

Complications separate by timing, and the timing is the most examinable single fact about each. Learn the clock, not just the list.[1]

Immediate (during and just after): the expected pain — sharp sting on freezing, throb for minutes after thaw — plus erythema and oedema at the site, occasional headache from the cold, and periauricular tinnitus when nitrogen gas vents through the Eustachian tube during treatment near the ear.[1]

Early (within 48 hours): blister formation — and this is expected; it confirms the freeze reached adequate depth, and the blister may be haemorrhagic. Do not deroof it. If large and painful, aspirate with a sterile needle and leave the roof intact as a biological dressing. Secondary infection and bleeding (more frequent on anticoagulants) are the other early events.[3]

Late (weeks to permanent): dominated by hypopigmentation, which is permanent — melanocytes died at warmer temperatures than keratinocytes, so the therapeutic freeze cleared them too, worst on the face and neck of Fitzpatrick IV-VI. Hyperpigmentation is post-inflammatory and usually fades over months. Scarring and atrophy follow over-aggressive or repeated freezing. Nail dystrophy follows over-aggressive periungual treatment, and nerve injury (usually transient) follows deep freezing near a superficial nerve.[9]

Recurrence is part of the complication picture: warts recur in 20-30%, and superficial BCC recurs in 5-15% of adequately treated low-risk lesions — exactly why BCC demands structured follow-up.[8]

The subtypes that bite

Plantar warts are painful, deeply set, and refractory. Pare the callus before freezing so the lethal isotherm reaches the viable wart tissue, hold the freeze longer than for a common wart, and combine with salicylic acid between sessions. Plantar warts carry the highest recurrence rate of any wart site.[6]

Periungual warts are technically difficult and dangerous. Over-aggressive freezing risks permanent nail dystrophy, and cryotherapy is relatively contraindicated in Raynaud or digital ischaemia because of digit-threatening vasospasm. Where treatment is unavoidable, freeze briefly and protect the nail fold — or step up to topical, intralesional bleomycin, or laser.[3]

Genital warts are not a primary-care spray job. First-line is topical podophyllotoxin or imiquimod; cryotherapy, when used, is a specialist procedure because the tissue is sensitive and scarring in a sexually significant site is a real harm. Molluscum contagiosum in children clears with a brief 5-10 second freeze, but counsel parents about hypopigmentation — and because molluscum is self-limiting, watchful waiting is often the kinder choice.[10]

Keloids and hypertrophic scars can be softened with a light freeze combined with intralesional corticosteroid, though recurrence is common. Cutaneous leishmaniasis is treated with cryotherapy in some endemic regions on the rationale that freezing kills the parasite — the evidence base is thin and lesion selection matters.[1]

The bedside round — before you pull the trigger

The pre-treatment assessment is brief but decisive. Confirm the diagnosis clinically and, for any pigment, dermoscopically; measure the lesion and note its thickness; map the site against sensitive structures (eye, nail unit, nerve, cartilage); record the phototype; and screen for cold-intolerance. Dermoscopy is mandatory for any pigmented lesion before a destructive treatment — the cost is seconds, the alternative is a destroyed melanoma. A baseline photograph, especially for BCC and Bowen, documents the pre-treatment appearance and anchors follow-up.[1]

Investigations are few. The only pre-treatment "test" is the question does this need a biopsy first? — answered yes whenever the diagnosis is in doubt, the lesion is pigmented, a malignant or premalignant label has not been histologically confirmed, or a treated lesion recurs. When cold-intolerance is suspected, send cryoglobulins, cold agglutinin titre, full blood count, and complement. For superficial BCC managed by cryotherapy, plan a 3-6 month review with photography and a low threshold to biopsy.[8]

For most indications, documentation is the investigation: lesion, site, freeze time per cycle, number of cycles, and the ice-ball halo size. It protects patient and clinician alike, and for BCC and Bowen it is what the follow-up decision hangs on.[3]

The technique, step by step

Standard open-spray technique, in order: clean the lesion and surrounding skin; position the nozzle 1-2 cm away; release a continuous or pulsed spray, painting the freeze across the lesion until a uniform ice ball extends 2-3 mm beyond the visible margin; stop and allow complete thaw to body temperature and normal colour — that is one freeze-thaw cycle. One or two cycles for benign lesions; two cycles for premalignant and malignant. Repeat sessions at 2-4 week intervals, most often every 3-4 weeks for warts.[2]

[2]

Dosimetry is judged by two visible endpoints: the size of the ice ball (the halo beyond the margin) and the freeze time (timed from the moment the ice ball reaches the lesion edge, not from when the trigger is pressed). A uniform glistening white disc with a sharp margin means adequate freeze; a mottled or incomplete freeze under-treats. For malignancy, where depth matters, some units place a thermocouple needle beneath the lesion to confirm the lethal isotherm — routine in specialist cryosurgery, rare in primary care.[1]

Analgesia is usually unnecessary for short benign freezes. For sensitive sites (digits, genitalia, periungual) or the long freezes of superficial BCC, use topical anaesthetic under occlusion or an injected local block. Children benefit from distraction and, where available, vapocoolant spray. Operator safety is non-negotiable: eye protection for operator and assistant (a ricocheting spray can freeze the cornea), gloves when handling the dewar, and never spray towards the face. Store liquid nitrogen upright in a ventilated room — it expands almost 700-fold as it vaporises and can displace oxygen in a confined space.[3]

Aftercare — what you tell the patient

Clear aftercare is part of competent practice and is examinable. Wash the area normally and apply a simple emollient such as white soft paraffin if crusted. The blister at 24-48 hours is expected — leave it intact; if large and painful, aspirate with a sterile needle and keep the roof as a biological dressing. The crust falls off over 1-3 weeks and must not be picked. Sun protection during healing reduces post-inflammatory hyperpigmentation, though it cannot prevent the intrinsic hypopigmentation. Warn every patient that the final result is a lighter macule — and in dark skin, an obviously lighter one.[3]

The natural history worth quoting at the bedside: pain and erythema immediately, blister within 24-48 hours (often haemorrhagic), crust at 7-14 days that sloughs to a pink then hypopigmented macule, and a settled hypopigmented scar by 4-6 weeks. Clearance rates: warts clear in roughly 50-70% after 3-4 sessions (recurrence 20-30%); most AK clear after one adequate freeze; superficial BCC cleared by cryotherapy recurs in 5-15%, mandating 3-6 month review.[8]

Evidence, guidelines, and where regions differ

The 2025 In Vivo review by Mokbel and colleagues consolidates the modern position: a versatile, cost-effective destructive modality spanning benign, premalignant, and carefully selected malignant lesions — provided the operator respects dose, cycle number, halo size, and contraindication. The technique papers examiners cite for ice-ball margin, cycle number, and freeze time are Ashique and colleagues (2021) and Cranwell and Sinclair (2017).[1][2][3]

For warts, the VRAIE pragmatic multicentre RCT (Chanal, 2025) found no single agent clearly superior among salicylic acid, liquid nitrogen, 5-fluorouracil, and imiquimod in previously-treated plantar warts — confirming that plantar warts are stubborn and treatment is patient-tailored. For actinic keratosis, the Worley (2023) systematic review and Dianzani (2020) review establish that cryotherapy, field therapy, and PDT are comparably effective per lesion, with field therapy preferred at high lesion count. For BCC, the European consensus guidelines (Peris, 2019) reserve cryotherapy for low-risk superficial lesions alongside imiquimod, 5-FU, and PDT, with surgery first-line.[7][5][4][8]

[1]

The controversies mirror the evidence: the best modality for plantar warts remains unsettled; the role of cryotherapy versus excision for superficial BCC is debated (most reserve it for low-risk lesions in patients unsuitable for surgery); field cancerisation increasingly goes to topical field therapy; and the over-use of cryotherapy on dark skin without counselling about hypopigmentation is a recurring medico-legal issue.[9]

Exam pearls

Ward-round test — three stems, thirty seconds each

Stem 1 — the back 'wart' the GP wants frozen (answer)

A GP calls about a 60-year-old, dark-skinned man with a new, darkly and irregularly pigmented "wart" on his back that he wants frozen off. The GP has not dermoscoped it. What do you say? Model: No — do not freeze. A pigmented lesion in an older adult is melanoma until dermoscopy and biopsy prove otherwise, and cryotherapy destroys tissue and forfeits the histology specimen. The correct pathway is dermoscopy now, then excisional biopsy for histology and staging. Freezing would destroy the specimen, make the margins unknowable, and delay the diagnosis of a potentially fatal disease. The single most dangerous cryotherapy error is treating a melanoma disguised as a "wart" or "seborrhoeic keratosis".[1]

Stem 2 — the freezer that will not stop bleeding (answer)

A nurse freezes a wart on the hand of a 70-year-old on warfarin; the site blisters and oozes blood over the next 24 hours. What went wrong, and what is the aftercare? Model: Anticoagulation is a relative caution — bleeding and haemorrhagic blistering are more frequent on warfarin, and the history should have been taken before freezing. The blister itself is expected and confirms adequate freeze depth: do not deroof it. Aspirate with a sterile needle if large and painful, leaving the roof as a biological dressing, apply a simple emollient, and safety-net for secondary infection. Check the INR, and document the lesion, freeze time, cycles, and halo.[3]

Stem 3 — the hypopigmented face (answer)

A 35-year-old woman of South Asian descent returns furious six weeks after you froze a solar lentigo on her cheek: she now has a chalk-white patch where the lentigo was. What happened, and what do you tell her? Model: This is permanent hypopigmentation — the signature complication. Melanocytes are more cold-sensitive than keratinocytes, so the therapeutic freeze ablated the melanocyte population at the site, and in Fitzpatrick IV-VI skin the result is a cosmetically obvious, permanent lighter macule. It will not repigment. Acknowledge the harm honestly, offer camouflage makeup, and refer for consideration of excision or pigment-transfer techniques if cosmetically disabling. The lesson for next time: in skin of colour at a visible site, counsel explicitly, photograph before, and prefer alternatives (laser, topical) — cryotherapy on dark facial skin is a relative contraindication for exactly this reason.[9]

References

1. [1]Mokbel R, Kodresko A, Mokbel K, et al. Cutaneous Cryosurgery in Dermatology: Evolving Principles and Clinical Applications for Benign, Premalignant, and Malignant Lesions In Vivo, 2025.PMID 40010951
2. [2]Ashique KT, Kaliyadan F, Jayasree P. Cryotherapy: Tips and Tricks J Cutan Aesthet Surg, 2021.PMID 34566372
3. [3]Cranwell WC, Sinclair R. Optimising cryosurgery technique Aust Fam Physician, 2017.PMID 28472571
4. [4]Dianzani C, Conforti C, Giuffrida R, et al. Current therapies for actinic keratosis Int J Dermatol, 2020.PMID 32012240
5. [5]Worley B, Harikumar V, Reynolds K, et al. Treatment of actinic keratosis: a systematic review Arch Dermatol Res, 2023.PMID 36454335
6. [6]Mulhem E, Pinelis S. Treatment of nongenital cutaneous warts Am Fam Physician, 2011.PMID 21842775
7. [7]Chanal J, Aubin F, Penso-Assathiany D, et al. A multicentre pragmatic randomized controlled trial comparing 50% salicylic acid, liquid nitrogen, 5% 5-fluorouracil cream, and 5% imiquimod cream in previously treated plantar warts. The VRAIE (VeRrues plAntaIres en villE) study Ann Dermatol Venereol, 2025.PMID 40743833
8. [8]Peris K, Fargnoli MC, Garbe C, et al. Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines Eur J Cancer, 2019.PMID 31288208
9. [9]Plensdorf S, Livieratos M, Dada N. Pigmentation Disorders: Diagnosis and Management Am Fam Physician, 2017.PMID 29431372
10. [10]Leung AKC, Barankin B, Hon KLE. Molluscum Contagiosum: An Update Recent Pat Inflamm Allergy Drug Discov, 2017.PMID 28521677