Cryotherapy (Liquid Nitrogen Treatment)

1. Clinical Overview

Summary

Cryotherapy is one of the most commonly performed dermatological procedures worldwide, utilizing extreme cold—most frequently liquid nitrogen at -196°C—to selectively destroy abnormal or unwanted tissue through controlled freezing. [1] The therapeutic principle relies on the formation of intracellular and extracellular ice crystals, which cause direct mechanical cell injury, membrane disruption, vascular stasis, and subsequent tissue necrosis. [2] Cryotherapy is indicated for a broad spectrum of benign, premalignant, and selected superficial malignant skin lesions including viral warts, seborrhoeic keratoses, actinic keratoses, dermatofibromas, and—in carefully selected cases—superficial basal cell carcinomas. [3]

The procedure offers numerous advantages: it is quick (often less than 5 minutes), relatively inexpensive, requires minimal equipment, can be performed in outpatient primary care or dermatology settings, and generally produces acceptable cosmetic outcomes. [4] No local anaesthesia is required for most applications, although the procedure is associated with varying degrees of discomfort during and after freezing. [5] Cryotherapy can be applied using either a spray gun (cryospray) or a cryoprobe, with spray techniques providing more precise control of freeze depth. [6]

Critical to successful cryotherapy is understanding the freeze-thaw cycle: a single freeze-thaw cycle is adequate for most benign lesions, while aggressive freeze-thaw-freeze (double freeze-thaw, or "FTF") cycles are indicated for premalignant and malignant lesions where deeper tissue destruction is required. [7] The clinical endpoint is typically the formation of a white ice ball extending 1–2 mm beyond the visible lesion margin. [8]

Side effects are common and predictable. Immediate pain and a burning sensation occur during freezing, followed by erythema, oedema, and blistering within hours. [9] The most significant long-term complication is permanent hypopigmentation, which occurs due to selective cryosensitivity of melanocytes. [10] This is particularly problematic in patients with darker skin (Fitzpatrick types IV–VI), and thorough informed consent regarding pigmentary changes is essential. [11]

Contraindications include cold urticaria (risk of systemic anaphylaxis), cryoglobulinaemia, Raynaud's phenomenon, peripheral vascular disease in the area of treatment, and locations overlying superficial nerves or tendons where permanent damage may result. [12] Cryotherapy should never be performed on lesions suspicious for melanoma, as tissue destruction precludes histological diagnosis and may delay potentially life-saving treatment. [13]

Key Facts

• Agent: Liquid nitrogen (N₂) at -196°C is the most common cryogen
• Mechanism: Intracellular ice formation → osmotic shifts → membrane rupture → vascular stasis → ischaemic necrosis [2,14]
• Indications: Viral warts, seborrhoeic keratoses, actinic keratoses, molluscum contagiosum, solar lentigines, dermatofibromas, superficial BCC (selected cases)
• Technique: Spray gun (most common) or cryoprobe; freeze-thaw-freeze (FTF) for aggressive treatment
• Freeze Times: 5–10 seconds for benign lesions; 10–20 seconds × 2 cycles for premalignant; 20–30 seconds × 2 cycles for superficial malignancies [15]
• Side Effects: Pain, blistering (haemorrhagic or serous), hypopigmentation (may be permanent), scarring (uncommon)
• Contraindications: Cold urticaria, cryoglobulinaemia, melanoma suspicion, overlying nerves/tendons
• Caution: Dark-skinned patients (high risk permanent hypopigmentation), children (anxiety/pain), lesions on fingers/toes (nail matrix damage)
• Cure Rates: Warts 60–80% (multiple treatments often needed); AK > 85%; superficial BCC 85–95% (but histological clearance unconfirmed) [16,17,18]
• Follow-Up: Review at 2–4 weeks; lesions should slough by 2–3 weeks; repeat treatment if residual

Clinical Pearls

"Freeze-Thaw-Freeze for Premalignant and Malignant": Double freeze-thaw cycles (FTF) significantly increase depth and completeness of tissue destruction, essential for AK, Bowen's disease, and superficial BCC. [7]

"White Halo = Endpoint": Freeze until a white ice ball (halo of frost) extends 1–2 mm beyond the lesion margin. This ensures adequate lateral spread of freezing. [8]

"Hypopigmentation is Permanent": Melanocytes are exquisitely sensitive to cold injury. Counsel all patients—especially those with darker skin—about the risk of permanent white marks. [10,11]

"Never Freeze Over a Nerve": Avoid cryotherapy over superficial nerves (lateral digits, temple, ulnar groove) due to risk of permanent neuropathy. [19]

"Debride First for Warts": Pare down hyperkeratotic warts before freezing to allow better penetration of cold into the lesion base. [20]

"Pain Lasts Hours, Not Days": Throbbing pain for 12–24 hours post-procedure is normal; simple analgesia (paracetamol/ibuprofen) is usually adequate. [9]

"Leave the Blister Intact": Haemorrhagic or serous blisters form within 24–48 hours—advise patients NOT to rupture them to reduce infection risk. [9]

"Multiple Sessions for Warts": Clearance rates for common warts with a single treatment are low (~50–60%); most require 2–4 sessions at 2–3 week intervals. [16]

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2. Epidemiology

Global Use

Cryotherapy is one of the most frequently performed dermatological procedures worldwide. It is particularly popular in primary care, dermatology, and minor surgery settings due to its accessibility, low cost, and minimal equipment requirements. [1] In the UK, cryotherapy is routinely performed in general practice for benign and premalignant lesions. [21] In the United States, cryotherapy is the most common destructive modality for actinic keratoses and viral warts. [22]

Indications by Category

Patient Demographics

Cryotherapy is performed across all age groups, though certain lesions predominate in specific populations:

• Children and adolescents: Viral warts, molluscum contagiosum [23]
• Adults (middle-aged): Seborrhoeic keratoses, dermatofibromas
• Elderly: Actinic keratoses, seborrhoeic keratoses, solar lentigines [24]

Skin Type Considerations

Patients with darker skin (Fitzpatrick types IV–VI) are at significantly higher risk of permanent hypopigmentation due to melanocyte sensitivity to cold injury. [10,11] Careful patient selection, informed consent, and potentially alternative treatments (e.g., topical therapy for AK) should be considered in this population.

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3. Pathophysiology

Mechanism of Cryonecrosis

Cryotherapy destroys tissue through multiple overlapping mechanisms: [2,14,25]

1. Intracellular Ice Formation (Primary Mechanism)

• Rapid freezing causes intracellular water to crystallize into sharp ice crystals
• Ice crystals physically puncture cell membranes and organelles (mechanical disruption)
• Osmotic injury: As extracellular ice forms, the extracellular space becomes hypertonic, drawing water out of cells
• This leads to cell dehydration, shrinkage, and membrane rupture

Exam Detail: Molecular Basis: Ice nucleation begins at approximately -10°C, but effective cell death requires temperatures of -40°C to -50°C. Malignant cells are generally more susceptible to cryoinjury than normal cells, possibly due to higher intracellular water content and increased membrane permeability. [14,26]

2. Vascular Stasis and Microcirculatory Failure

• Endothelial injury leads to capillary and venule thrombosis
• Vasospasm and loss of vascular perfusion result in ischaemic necrosis
• This "delayed" effect occurs over 24–48 hours post-treatment and extends tissue destruction beyond the initial freeze zone [27]

3. Immunological Response

• Release of cellular antigens from destroyed tissue may trigger an immune response
• Possible immune-mediated clearance of residual abnormal cells (e.g., HPV-infected keratinocytes in warts)
• This may explain delayed clearance and occasional "bystander" lesion resolution [28]

4. Apoptosis

• Sublethally injured cells undergo programmed cell death (apoptosis) over 48–72 hours
• Contributes to tissue clearance without significant inflammation [29]

The Freeze-Thaw Cycle

Single Freeze-Thaw Cycle:

1. Freezing phase: Liquid nitrogen applied until white ice ball forms 1–2 mm beyond lesion edge
2. Thaw phase: Allow complete passive thaw (typically 1–2 minutes for small lesions)
3. Used for benign lesions (warts, seborrhoeic keratoses)

Double Freeze-Thaw-Freeze (FTF) Cycle:

1. First freeze: Freeze to white halo
2. First thaw: Allow complete passive thaw
3. Second freeze: Re-freeze to same endpoint
4. The second freeze is MORE destructive due to recrystallization injury and cumulative vascular damage [7,30]
5. Used for premalignant and malignant lesions

Clinical Pearl: Why Thaw Completely? Allowing full thaw between freeze cycles permits recrystallization of ice, which causes additional cell membrane shearing. Incomplete thaw reduces the efficacy of the second freeze. [30]

Temperature Thresholds

Depth of Freeze: The depth of tissue destruction is proportional to:

• Freeze time (longer = deeper)
• Pressure applied (for probe techniques)
• Number of freeze-thaw cycles (FTF > single)
• Lesion vascularity (well-vascularized lesions thaw faster, may need longer freeze times)

Tissue Response Timeline

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4. Clinical Presentation (Indications)

Lesions Suitable for Cryotherapy

Viral Warts (Verrucae)

Common Warts (Verruca vulgaris):

• Rough, hyperkeratotic papules on hands, fingers, knees
• Caused by HPV (types 2, 4, 27, 57)
• Freeze time: 10–15 seconds, FTF cycle
• Cure rate: 60–80% (often requires 2–4 treatments) [16]
• Tip: Debride hyperkeratotic surface with scalpel blade before freezing [20]

Plantar Warts:

• Painful warts on weight-bearing areas of feet
• Often deep with overlying callus
• Freeze time: 15–20 seconds, FTF cycle
• Cure rate: Lower than common warts (~50–60%) [16]
• Tip: Aggressive paring before cryotherapy improves penetration

Filiform Warts:

• Finger-like projections on face, neck, eyelids
• Freeze time: 5–10 seconds (brief, to avoid scarring on face)

Seborrhoeic Keratoses

• Benign, "stuck-on" brown/black warty lesions
• Common in middle-aged and elderly
• Freeze time: 5–10 seconds, single cycle
• Outcome: Excellent cosmesis; lesions usually fall off within 2 weeks
• Tip: Warn patient of temporary hypopigmentation [31]

Actinic Keratoses (AK)

• Premalignant lesions caused by chronic UV exposure
• Rough, scaly, erythematous macules/papules on sun-exposed areas (face, scalp, hands, forearms)
• Risk of progression to SCC: ~5–10% over lifetime [32]
• Freeze time: 10–20 seconds, FTF cycle (double freeze-thaw)
• Cure rate: 85–95% for single lesions [17]
• Advantage over topical therapy: Immediate, single-session treatment
• Disadvantage: Does not treat "field cancerization" (subclinical AK in surrounding skin) [33]

Evidence Debate: Field Therapy vs. Lesion-Directed Therapy: While cryotherapy effectively treats visible AK, it does not address the surrounding field of actinic damage where subclinical AK may exist. Topical field therapies (5-FU, imiquimod, ingenol mebutate) treat both visible and subclinical lesions but require patient adherence and cause significant inflammation. [33,34] Combination approaches may be optimal for patients with multiple AK.

Superficial Basal Cell Carcinoma (BCC)

• Selected cases only: Low-risk, superficial BCC on trunk or limbs
• NOT recommended for: High-risk sites (face, ears, scalp); morphoeic or infiltrative BCC subtypes; recurrent BCC
• Freeze time: 20–30 seconds, FTF cycle, with 3–5 mm clinical margin [35]
• Cure rate: 85–95%, but histological clearance cannot be confirmed (unlike excision)
• Follow-up: Close clinical surveillance for recurrence [18]

Clinical Pearl: BCC Cryotherapy is Controversial: While cure rates are high for carefully selected superficial BCC, most dermatology and skin cancer guidelines recommend surgical excision as first-line due to histological confirmation of clearance. Cryotherapy may be appropriate in elderly patients with low-risk lesions where surgery is not feasible. [18,35]

Bowen's Disease (SCC In Situ)

• Freeze time: 15–20 seconds, FTF cycle
• Alternative: Topical 5-FU, imiquimod, or excision
• Cure rate: ~80–85% [36]

Dermatofibromas

• Benign dermal nodules (histiocytic proliferation)
• Cryotherapy can flatten but rarely completely removes them
• Freeze time: 10–15 seconds
• Outcome: Lesion becomes less palpable but may persist

Molluscum Contagiosum

• Viral infection (poxvirus) causing small umbilicated papules
• Common in children
• Freeze time: 5–10 seconds (brief, to minimize pain and scarring)
• Cure rate: Moderate; spontaneous resolution also occurs [23]
• Alternative: Curettage, cantharidin

Solar Lentigines ("Age Spots"

• "Liver Spots")

• Benign pigmented macules from chronic sun exposure

• Freeze time: 5–10 seconds (cosmetic indication)

• Risk: Hypopigmentation or hyperpigmentation [37]

Contraindications

Absolute Contraindications

Relative Contraindications

Poor Prognostic Lesions for Cryotherapy

• Large warts (> 1 cm): Poor penetration of freeze
• Plantar warts: Thick overlying callus limits efficacy
• Recurrent or treatment-resistant warts: Consider alternative (e.g., topical salicylic acid, curettage, immunotherapy)
• Nodular or infiltrative BCC: Inadequate depth of freeze; surgical excision mandatory

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5. Clinical Examination (Pre-Procedure Assessment)

Clinical Assessment

1. Confirm Diagnosis

• Visual inspection: Morphology, colour, surface characteristics
• Dermoscopy: May aid diagnosis of uncertain lesions (e.g., seborrhoeic keratosis vs. melanoma)
• Rule out melanoma: Any pigmented lesion with ABCDE features (Asymmetry, Border irregularity, Colour variation, Diameter > 6 mm, Evolution) should be biopsied, NOT frozen [13]

2. Document Lesion Characteristics

• Size: Measure diameter (mm)
• Location: Anatomical site (important for nerve/tendon considerations)
• Number: Single vs. multiple lesions
• Depth: Flat vs. raised vs. nodular (nodular lesions may not respond well)

3. Assess Skin Type

• Fitzpatrick skin type: Darker skin (types IV–VI) at higher risk of hypopigmentation [10,11]
• Patient expectations: Counsel about pigmentary changes

4. Check for Contraindications

• History of cold urticaria (rare; ask: "Do you get hives or swelling when exposed to cold?")
• Cryoglobulinaemia (usually known diagnosis; associated with hepatitis C, lymphoproliferative disorders)
• Raynaud's phenomenon (especially if freezing digits or extremities)
• Peripheral vascular disease (check pulses if lesion on lower limb)

5. Assess Anatomical Risk

• Superficial nerves: Lateral fingers (digital nerves), temple (facial nerve branches), ulnar groove (ulnar nerve) [19]
• Tendons: Avoid aggressive freezing directly over extensor tendons on hands

Informed Consent

Essential Discussion Points

1. Procedure:

   • "We will use very cold liquid nitrogen to freeze the lesion"
   • "You will feel a cold, burning sensation that lasts 10–30 seconds"
   • "The area may throb or ache for a few hours afterward"

2. Expected Outcomes:

   • "The lesion will blister, then scab over, and fall off in 2–3 weeks"
   • For warts: "Multiple treatments are often needed"

3. Side Effects:

   • Pain: During and after freezing (hours)
   • Blistering: Normal; may be blood-filled (haemorrhagic blister)
   • Hypopigmentation: "The treated area may become permanently lighter in colour" [10,11]
   • Scarring: Uncommon, but possible

4. Post-Procedure Care:

   • Keep clean, leave blister intact
   • Simple analgesia if needed
   • Return if signs of infection (increasing pain, pus, fever)

5. Follow-Up:

   • Review in 2–4 weeks
   • Repeat treatment may be needed

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6. Investigations

Pre-Procedure Investigations

Usually None Required

• Cryotherapy is a clinical diagnosis-based procedure
• Most benign and premalignant lesions (warts, seborrhoeic keratoses, AK) are diagnosed clinically

When to Investigate

Clinical Pearl: "Never Freeze What You Don't Know": If diagnosis is uncertain, biopsy first. Cryotherapy destroys tissue and precludes subsequent histological diagnosis. This is especially critical for pigmented lesions where melanoma must be excluded. [13]

Post-Procedure Follow-Up

• 2–4 weeks: Clinical review
  • Assess lesion clearance
  • Check for adverse effects (hypopigmentation, scarring, nerve injury)
  • Repeat treatment if residual lesion present
• 3–6 months: For premalignant/malignant lesions (AK, superficial BCC)
  • Monitor for recurrence
  • Long-term surveillance for BCC (annual skin checks)

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7. Procedure (Technique)

Equipment

1. Cryogen

• Liquid nitrogen (N₂) at -196°C (most common)
• Stored in insulated Dewar flask (vacuum flask)
• Alternative: Nitrous oxide (N₂O) cryoprobes (-89°C; less effective than liquid nitrogen but safer for small portable devices)

2. Application Method

Spray Gun (Cryospray):

• Most common method
• Handheld spray gun (e.g., CryoAc, Brymill CryoGun)
• Delivers fine spray of liquid nitrogen
• Allows precise control of freeze depth and lateral spread
• Advantages: Quick, precise, good for large or multiple lesions
• Disadvantages: Risk of spray drift; requires practice

Cryoprobe (Contact Method):

• Metal probe tip cooled by liquid nitrogen or nitrous oxide
• Applied directly to lesion
• Advantages: Precise application; minimal drift; good for lesions near eyes or sensitive structures
• Disadvantages: Slower freeze; less deep penetration than spray; requires good contact

Cotton-Tipped Applicator:

• Cotton bud dipped in liquid nitrogen and applied to lesion
• Advantages: Cheap, simple, portable
• Disadvantages: Inconsistent freeze depth; rapid warming of applicator; poor for deep or large lesions
• Best for: Small, superficial lesions (e.g., molluscum)

3. Protective Equipment

• Gloves: Insulated gloves for operator
• Eye protection: Safety goggles if using spray near eyes
• Vaseline: Applied to peri-lesional normal skin to protect from cold injury

Pre-Procedure Preparation

1. Debride hyperkeratotic lesions:

   • Use scalpel blade to pare down thick wart or AK surface
   • Improves penetration of cold [20]

2. Protect surrounding skin:

   • Apply Vaseline to normal skin around lesion
   • Use cardboard or metal shields for spray techniques (to limit lateral spread)

3. Position patient:

   • Comfortable, well-lit position
   • Warn patient about cold sensation and brief pain

Cryotherapy Technique

Step-by-Step Procedure

┌─────────────────────────────────────────────────────────────────┐
│              CRYOTHERAPY PROCEDURE (SPRAY METHOD)               │
├─────────────────────────────────────────────────────────────────┤
│                                                                 │
│  1. PREPARATION:                                                 │
│     • Confirm diagnosis and obtain consent                      │
│     • Debride hyperkeratotic lesions if needed                  │
│     • Apply Vaseline to peri-lesional skin                      │
│                                                                 │
│  2. SPRAY APPLICATION:                                           │
│     • Hold spray gun perpendicular, 1–2 cm from lesion          │
│     • Start spray; apply continuous, focused stream             │
│     • Observe WHITE ICE BALL forming                            │
│     • Continue until ice ball extends 1–2 mm beyond lesion edge │
│     • Stop spray                                                │
│                                                                 │
│  3. FREEZE TIME (from start of ice ball formation):              │
│     • Benign (warts, SK):           5–10 seconds                │
│     • Premalignant (AK):            10–20 seconds               │
│     • Superficial BCC:              20–30 seconds               │
│                                                                 │
│  4. THAW PHASE:                                                  │
│     • Allow COMPLETE passive thaw (1–3 minutes)                 │
│     • Lesion will become soft and normal colour returns         │
│                                                                 │
│  5. SECOND FREEZE (FTF CYCLE) — if indicated:                    │
│     • Repeat freeze to same endpoint (1–2 mm white halo)        │
│     • Same freeze time as first cycle                           │
│                                                                 │
│  6. POST-PROCEDURE:                                              │
│     • No dressing usually required                              │
│     • Advise patient about expected blister formation           │
│     • Provide written instructions (see below)                  │
│                                                                 │
└─────────────────────────────────────────────────────────────────┘

Freeze Times by Lesion Type

Clinical Pearl: Clinical Endpoint: The visible "white halo" represents the -20°C isotherm. To achieve the -40 to -50°C necessary for reliable cell kill, the freeze must extend 1–2 mm beyond the lesion edge. [8,15]

Special Techniques

Cone-Spray Technique (for Warts)

• Use disposable plastic cone (otoscope speculum) over wart
• Spray into cone, creating confined freeze zone
• Protects surrounding skin
• Useful for pediatric patients or difficult anatomical sites

Probe Technique

• For lesions near eyes, lips, or sensitive structures
• Direct contact with probe tip
• More controlled, less risk of collateral damage
• Requires 10–20 seconds longer freeze time (due to slower heat transfer)

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8. Post-Procedure Care

Expected Timeline of Healing

Patient Instructions

What to Expect

• Pain: Throbbing pain for 12–24 hours is normal
  • Take paracetamol or ibuprofen as needed [9]
• Blister: A blister (clear or blood-filled) will form within 24–48 hours
  • Do NOT pop the blister (risk of infection)
  • If it ruptures spontaneously, keep clean and dry
• Scab: Blister will dry out and form a crust/scab
  • Allow scab to fall off naturally (do not pick)
• Healing: Complete healing in 2–3 weeks

Wound Care

• Keep clean: Wash gently with soap and water
• No dressing required for most lesions
• If blister ruptures: Apply simple antiseptic and non-stick dressing

When to Seek Medical Advice

• Increasing pain after 48 hours (may indicate infection)
• Pus, spreading redness, fever (signs of infection)
• Severe blistering or unexpected reaction

Follow-Up

• Review in 2–4 weeks
• Repeat treatment may be needed if lesion persists

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9. Complications

Expected/Common (> 10%)

Pain

• During freezing: Burning, stinging sensation lasting 10–30 seconds [9]
• Post-procedure: Throbbing ache for 12–24 hours
• Management: Paracetamol, ibuprofen

Blistering

• Incidence: > 50% of treatments [9]
• Type: Serous (clear) or haemorrhagic (blood-filled)
• Onset: 6–48 hours post-treatment
• Management: Leave intact; allow to dry and resorb

Hypopigmentation

• Incidence: 20–50%, depending on skin type [10,11]
• Mechanism: Melanocytes are exquisitely sensitive to cold injury
• May be PERMANENT, especially in darker skin
• Prevention: Conservative freeze times in dark-skinned patients; thorough consent

Erythema and Oedema

• Universal; resolves within 48–72 hours

Uncommon (1–10%)

Hyperpigmentation

• Paradoxical darkening of treated area
• More common in darker skin types
• Usually temporary; resolves over months

Scarring

• Incidence: less than 5% [38]
• Risk factors: Over-aggressive freezing, poor wound care, infection
• Appearance: Atrophic scar, hypertrophic scar (rare)

Delayed Healing

• Particularly on lower limbs in elderly or those with venous insufficiency
• May take > 6 weeks to heal

Recurrence

• Warts: 20–40% recurrence rate [16]
• AK: 10–15% recurrence [17]
• BCC: 5–15% recurrence [18]
• Management: Repeat treatment or consider alternative modality

Rare (less than 1%)

Nerve Damage (Neuropathy)

• Permanent or prolonged neuropathy from freezing over superficial nerves [19]
• Sites at risk: Lateral digits (digital nerves), temple (facial nerve), ulnar groove (ulnar nerve)
• Symptoms: Numbness, paraesthesia, pain
• Prevention: Avoid cryotherapy at these sites

Tendon Damage

• Theoretical risk of tendon weakening or rupture
• Sites at risk: Extensor tendons on dorsum of hand
• Prevention: Avoid aggressive freezing directly over tendons

Infection

• Rare; less than 1%
• Usually secondary bacterial infection of ruptured blister
• Management: Oral antibiotics (flucloxacillin or erythromycin)

Cold Urticaria Reaction

• Systemic reaction in patients with undiagnosed cold urticaria [12]
• Symptoms: Widespread urticaria, angioedema, anaphylaxis (rare)
• Management: Cease treatment immediately; antihistamines; IM adrenaline if anaphylaxis

Nail Matrix Damage

• Cryotherapy near nail fold can damage nail matrix
• Sequelae: Permanent nail dystrophy, ridging, splitting
• Prevention: Avoid aggressive freezing on digits near nail bed

Cartilage Damage

• Theoretical risk on ears or nose
• Chondritis or cartilage necrosis reported in literature (rare)

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10. Prognosis & Outcomes

Cure Rates by Indication

Viral Warts

• Single treatment cure rate: 50–60% [16]
• After 2–4 treatments: 70–80%
• Plantar warts: Lower cure rate (~50–60%) due to thick overlying skin
• Recurrence: 20–40%
• Factors predicting poor response: Large size, plantar location, periungual location, immunosuppression

Seborrhoeic Keratoses

• Cure rate: > 95% [31]
• Single treatment usually adequate
• Excellent cosmetic outcome

Actinic Keratoses

• Cure rate: 85–95% for single lesions [17]
• Recurrence: 10–15% at 1 year
• Field therapy (topical 5-FU, imiquimod) may be superior for multiple AK or field cancerization [33,34]

Bowen's Disease (SCC In Situ)

• Cure rate: 80–85% [36]
• Recurrence: 10–20%
• Alternative: Excision (provides histological clearance)

Superficial Basal Cell Carcinoma

• Cure rate: 85–95% for carefully selected cases [18,35]
• Recurrence: 5–15% at 5 years
• Limitation: Histological clearance cannot be confirmed (unlike excision or Mohs surgery)
• Best use: Elderly patients, low-risk sites (trunk, limbs), small (less than 1 cm) superficial BCC

Evidence Debate: BCC Cryotherapy vs. Excision: Surgical excision remains the gold standard for BCC due to histological confirmation of clearance and lower recurrence rates. However, cryotherapy offers a reasonable alternative for elderly patients with low-risk, superficial BCC on the trunk or limbs where surgery may be impractical. Close clinical follow-up is mandatory. [18,35]

Cosmetic Outcomes

• Hypopigmentation: 20–50% (may be permanent) [10,11]
• Scarring: less than 5% [38]
• Overall cosmetic satisfaction: High for benign lesions; lower for facial lesions in dark-skinned patients

Factors Affecting Outcomes

Poor Prognostic Factors

• Large lesion size (> 1 cm)
• Deep or nodular lesions
• Plantar or palmar location (thick stratum corneum)
• Immunosuppression (organ transplant, HIV) — lower cure rates for warts and higher recurrence for skin cancers
• Dark skin type — higher complication rate (hypopigmentation)

Good Prognostic Factors

• Small, superficial lesions
• Early treatment (warts and premalignant lesions)
• Appropriate freeze time and technique (FTF for aggressive lesions)

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11. Evidence & Guidelines

Key Guidelines

1. British Association of Dermatologists (BAD)

• Guideline: Management of Actinic Keratoses (2017)
• Recommendation: Cryotherapy is first-line for isolated AK; field therapy for multiple AK [17,33]

2. National Institute for Health and Care Excellence (NICE)

• Guideline: Skin Cancer Prevention (2016)
• Recommendation: Cryotherapy appropriate for low-risk, non-melanoma skin cancers with close follow-up

3. American Academy of Dermatology (AAD)

• Guideline: Management of Actinic Keratoses (2021)
• Recommendation: Cryotherapy, topical therapy, or photodynamic therapy for AK [34]

4. European Dermatology Forum (EDF)

• Guideline: Basal Cell Carcinoma (2020)
• Recommendation: Surgical excision preferred; cryotherapy only for low-risk, superficial BCC in elderly or poor surgical candidates [35]

Key Evidence

Actinic Keratoses

1. Thai et al. (2004) — Randomized trial of cryotherapy vs. topical 5-FU for AK

   • Finding: Both effective; cryotherapy more painful but faster; 5-FU more irritation but treats field [39]

2. Kaufmann et al. (2008) — Systematic review of AK treatments

   • Finding: Cryotherapy clearance rate 75–88%; topical therapy 50–70%; PDT 70–80% [34]

Viral Warts

3. Kwok et al. (2012) — Cochrane review of wart treatments

   • Finding: Cryotherapy cure rate 50–70%; no single treatment superior; multiple treatments improve outcomes [16]

4. Bruggink et al. (2010) — RCT of cryotherapy vs. salicylic acid for warts

   • Finding: No significant difference in cure rates; combination therapy no better than monotherapy [40]

Basal Cell Carcinoma

5. Kuflik et al. (1991) — Long-term follow-up of cryotherapy for BCC

   • Finding: 5-year cure rate 92% for primary superficial BCC; recurrence higher for nodular BCC [18]

6. Thissen et al. (2000) — Comparison of cryotherapy vs. excision for BCC

   • Finding: Excision superior for nodular BCC; cryotherapy acceptable for superficial BCC in selected cases [35]

Seborrhoeic Keratoses

7. Kuflik (1994) — Case series of cryotherapy for seborrhoeic keratoses
   • Finding: 95% clearance with minimal scarring [31]

Complications

8. Holt (1988) — Survey of cryotherapy complications

   • Finding: Hypopigmentation 20–50%; permanent in many cases; higher in darker skin [10]

9. Sonnex et al. (1982) — Nerve damage from cryotherapy

   • Finding: Neuropathy reported in 1–2% of digital treatments [19]

Mechanism

10. Gage et al. (1985) — Review of cryobiology and cryosurgery

    • Finding: Cell death reliable at -40°C to -50°C; double freeze-thaw significantly increases necrosis depth [14]

11. Hoffmann et al. (2001) — Immunological effects of cryotherapy

    • Finding: Cryotherapy induces systemic immune response to tumor antigens (abscopal effect) [28]

Evidence Summary Table

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12. Examination Focus

Viva Questions & Model Answers

Q1: What is the mechanism of tissue destruction in cryotherapy?

Model Answer: "Cryotherapy destroys tissue through multiple mechanisms. The primary mechanism is intracellular ice crystal formation during rapid freezing, which causes direct mechanical disruption of cell membranes and organelles. [2] As extracellular ice forms, the extracellular space becomes hypertonic, drawing water out of cells and causing osmotic injury and dehydration. Additionally, cryotherapy induces vascular stasis and microthrombosis, leading to ischaemic necrosis that extends tissue destruction beyond the initial freeze zone over 24–48 hours. [27] Finally, sublethally injured cells undergo apoptosis over 48–72 hours, contributing to tissue clearance. [29] Effective cell death requires temperatures of -40°C to -50°C at the target site. [14]"

Q2: What is the freeze-thaw-freeze (FTF) cycle, and when is it indicated?

Model Answer: "The freeze-thaw-freeze cycle involves two consecutive freeze-thaw cycles applied to the same lesion. After the initial freeze (until a white ice ball extends 1–2 mm beyond the lesion), the tissue is allowed to completely thaw passively, then re-frozen to the same endpoint. [7] The second freeze is more destructive due to recrystallization injury during thawing, which causes additional cell membrane shearing. [30] FTF cycles are indicated for premalignant and malignant lesions such as actinic keratoses, Bowen's disease, and superficial basal cell carcinomas, where deeper and more complete tissue destruction is required. [7,15] Benign lesions like seborrhoeic keratoses typically require only a single freeze-thaw cycle."

Q3: What are the contraindications to cryotherapy?

Model Answer: "Absolute contraindications include cold urticaria, which carries a risk of systemic anaphylaxis [12]; cryoglobulinaemia, where abnormal proteins precipitate in cold temperatures causing thrombosis and ischaemia; suspected melanoma, as tissue destruction precludes histological diagnosis and may delay life-saving treatment [13]; and unknown diagnosis, where biopsy is mandatory before any destructive therapy.

Relative contraindications include Raynaud's phenomenon (risk of worsening vascular spasm) [12]; peripheral vascular disease (risk of non-healing ulcer or gangrene); dark skin (Fitzpatrick types IV–VI) due to high risk of permanent hypopigmentation [10,11]; lesions overlying superficial nerves (e.g., lateral digits, temple) where permanent neuropathy may occur [19]; and lesions overlying tendons, where rupture is theoretically possible."

Q4: What is the risk of hypopigmentation, and how do you counsel patients?

Model Answer: "Hypopigmentation is one of the most common long-term complications of cryotherapy, occurring in 20–50% of cases, and it may be permanent. [10,11] The mechanism is selective cryosensitivity of melanocytes, which are damaged or destroyed at lower temperatures than keratinocytes. The risk is significantly higher in patients with darker skin (Fitzpatrick types IV–VI). [11]

I would counsel patients by explaining: 'The treated area may become permanently lighter in colour than the surrounding skin. This is because the freezing can damage the pigment-producing cells. This risk is higher in people with darker skin, and the change may be permanent. In some cases, the area may also become darker instead.' I would document this discussion and ensure the patient understands and accepts this risk before proceeding, particularly for cosmetically sensitive areas like the face."

Q5: What are the cure rates and limitations of cryotherapy for superficial basal cell carcinoma?

Model Answer: "Cryotherapy for carefully selected superficial BCC has a cure rate of 85–95% at 5 years, with recurrence rates of 5–15%. [18,35] However, cryotherapy has significant limitations:

First, histological clearance cannot be confirmed, unlike surgical excision or Mohs micrographic surgery, meaning we cannot be certain the lesion has been completely removed. Second, it is only appropriate for low-risk, superficial BCC on the trunk or limbs—not for high-risk sites like the face, ears, or scalp, and not for nodular or morphoeic subtypes. [35] Third, close clinical surveillance is mandatory to detect recurrence.

For these reasons, surgical excision remains the gold standard for most BCCs. [35] Cryotherapy is best reserved for elderly patients with low-risk lesions where surgery is impractical or contraindicated."

Q6: How does cryotherapy compare to topical field therapy for actinic keratoses?

Model Answer: "Both cryotherapy and topical field therapies (5-FU, imiquimod, ingenol mebutate) are effective for actinic keratoses, but they have different advantages. [33,34]

Cryotherapy is lesion-directed: it treats individual visible AK with clearance rates of 85–95%. [17] It is a single-session treatment, which is convenient and ensures adherence. However, it does not treat field cancerization—the surrounding subclinical actinic damage where future AK may develop. [33]

Topical field therapies treat both visible and subclinical lesions across a broad area, addressing field cancerization. [33,34] However, they require patient adherence over weeks to months and cause significant local inflammation (erythema, erosions, crusting) that may be poorly tolerated.

For single or few AK, cryotherapy is often first-line. For multiple AK or significant field cancerization, topical field therapy may be superior. Combination approaches—cryotherapy for thicker lesions plus topical therapy for the field—may be optimal in some patients. [34]"

Short Case Scenario

Scenario: A 72-year-old man presents with a scaly, erythematous patch on his left forearm, consistent with actinic keratosis. You plan cryotherapy.

Examiner Questions:

1. How would you perform cryotherapy for this lesion?
2. What freeze time and cycle would you use?
3. What are the expected side effects?

Model Answer:

1. "I would first confirm the diagnosis clinically—a rough, scaly, erythematous patch on a sun-exposed site in an elderly patient is consistent with actinic keratosis. I would obtain informed consent, explaining the procedure, expected outcomes, and risks including pain, blistering, and hypopigmentation. I would debride any hyperkeratotic scale, then apply liquid nitrogen using a spray gun, freezing until a white ice ball extends 1–2 mm beyond the lesion margin. [8]"

2. "For actinic keratosis, I would use a freeze-thaw-freeze (FTF) cycle with a freeze time of 10–20 seconds per cycle. [17] This ensures deeper tissue destruction appropriate for a premalignant lesion. I would allow complete passive thaw between cycles. [7]"

3. "The patient should expect immediate pain and a burning sensation during freezing. Within 24–48 hours, a blister will form—either clear or blood-filled—which is normal. [9] The area may throb for 12–24 hours, and I would recommend paracetamol. The blister will dry and form a scab over 1–2 weeks, then fall off. There is a 20–50% risk of permanent hypopigmentation, which I would discuss before treatment. [10] I would review the patient in 2–4 weeks to assess clearance."

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13. Patient/Layperson Explanation

What is Cryotherapy?

Cryotherapy is a procedure where we use extremely cold liquid nitrogen to freeze and destroy unwanted or abnormal skin lesions, such as warts, sun-damaged spots, or benign growths. The cold temperature causes the cells in the lesion to die, and the lesion will fall off over the next few weeks.

Why Might I Need Cryotherapy?

Cryotherapy is used to treat:

• Warts (caused by a virus)
• Seborrhoeic keratoses (harmless brown "age spots")
• Actinic keratoses (scaly patches from sun damage that can rarely turn into skin cancer)
• Other benign skin lesions

What Happens During the Procedure?

1. Freezing: The doctor or nurse will spray or apply very cold liquid nitrogen to the lesion using a small handheld device.
2. Sensation: You will feel a sharp, cold, burning sensation for about 10–30 seconds. This can be uncomfortable, but it is brief.
3. Appearance: The area will turn white (frozen) during the procedure, then return to normal colour as it thaws.
4. Duration: The whole procedure usually takes less than 5 minutes.

What Happens After the Procedure?

• Pain: The area may throb or ache for a few hours afterward. Paracetamol or ibuprofen can help.
• Blister: Within 24–48 hours, a blister will form. This is normal and expected. The blister may be clear or filled with blood.
  • Do NOT pop the blister—leave it alone to reduce the risk of infection.
  • If it pops on its own, gently clean the area with soap and water and apply a simple dressing.
• Scab: The blister will dry out and form a crust or scab over the next few days.
• Healing: The scab will fall off on its own in 2–3 weeks, and the lesion should be gone.

Are There Any Risks or Side Effects?

Cryotherapy is very safe, but like all procedures, there are some possible side effects:

• Pain: Temporary pain during and after the procedure (common)
• Blister: Expected as part of healing
• Lightening of skin colour (hypopigmentation): The treated area may become permanently lighter than the surrounding skin. This is more common in people with darker skin tones. [10,11]
• Darkening of skin colour (less common): The area may temporarily or permanently darken.
• Scarring: Rare, but possible if the area becomes infected or is picked at.
• Infection: Very rare; keep the area clean.

Will I Need More Than One Treatment?

• Warts: Often need 2–4 treatments, spaced 2–3 weeks apart. [16]
• Seborrhoeic keratoses and sun spots: Usually just one treatment.
• Actinic keratoses: One or two treatments are usually enough.

How Do I Care for the Area After Treatment?

• Keep it clean: Wash gently with soap and water.
• Leave the blister alone: Do not pop it.
• Pain relief: Take paracetamol or ibuprofen if needed.
• No special dressing: Most lesions don't need a bandage unless the blister ruptures.

When Should I See the Doctor Again?

• Routine follow-up: 2–4 weeks after treatment to check healing and see if another treatment is needed.
• Urgent advice: Contact your doctor if you notice:
  • Increasing pain after 48 hours
  • Pus, spreading redness, or fever (signs of infection)
  • Any unexpected or worrying reaction

Is Cryotherapy Painful?

Most people describe the sensation as a sharp, cold "ice burn" that lasts 10–30 seconds during the freezing. There may be some throbbing afterward for a few hours, but this is usually mild and manageable with simple painkillers.

Will It Leave a Scar?

Scarring is rare (less than 5%) if the area heals well and is not picked at. [38] However, the treated area may be permanently lighter in colour (hypopigmentation), especially in people with darker skin. [10,11]

Can I Go Back to Normal Activities After Cryotherapy?

Yes, you can return to normal activities immediately after the procedure. There are no restrictions on exercise, bathing, or work.

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14. References

Primary Guidelines

1. Heppt MV, Steeb T, Ruzicka T, Berking C. Cryosurgery in dermatology. J Dtsch Dermatol Ges. 2018;16(12):1436-1446. DOI: 10.1111/ddg.13698. PMID: 30468302.

2. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37(3):171-186. DOI: 10.1006/cryo.1998.2115. PMID: 9787063.

3. Dawber R, Colver G, Jackson A. Cutaneous Cryosurgery: Principles and Clinical Practice. 3rd ed. London: Martin Dunitz; 2004.

4. Kuflik EG. Cryosurgery updated. J Am Acad Dermatol. 1994;31(6):925-944. DOI: 10.1016/s0190-9622(94)70264-0. PMID: 7962774.

5. Graham GF, Clark LC. Statistical analysis of cryosurgery for dermatologic lesions. Clin Dermatol. 1990;8(1):101-107. DOI: 10.1016/0738-081x(90)90075-j. PMID: 2347403.

6. Zouboulis CC. Cryosurgery in dermatology. Eur J Dermatol. 1998;8(7):466-474. PMID: 9854156.

7. Torre D. Cryosurgical treatment of epitheliomas using the cone-spray technique. J Dermatol Surg. 1977;3(4):432-434. DOI: 10.1111/j.1524-4725.1977.tb00261.x.

8. Kuflik EG, Gage AA. The five-year cure rate achieved by cryosurgery for skin cancer. J Am Acad Dermatol. 1991;24(6):1002-1004. DOI: 10.1016/0190-9622(91)70161-4. PMID: 1869688.

9. Bourke JF, Berth-Jones J, Hutchinson PE. Cryotherapy of common viral warts at intervals of 1, 2 and 3 weeks. Br J Dermatol. 1995;132(3):433-436. DOI: 10.1111/j.1365-2133.1995.tb08677.x. PMID: 7718462.

10. Holt PJA. Cryotherapy for skin cancer: results over a 5-year period using liquid nitrogen spray cryosurgery. Br J Dermatol. 1988;119(2):231-240. DOI: 10.1111/j.1365-2133.1988.tb03205.x. PMID: 3166944.

11. Grimes PE, Stockton T. Pigmentary disorders in blacks. Dermatol Clin. 1988;6(2):271-281. PMID: 3378377.

12. Wanderer AA, Grandel KE, Wasserman SI, Farr RS. Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes. J Allergy Clin Immunol. 1986;78(3):417-423. DOI: 10.1016/0091-6749(86)90027-x. PMID: 3760397.

13. Kuflik EG. Cryosurgery for cutaneous malignancy: an update. Dermatol Surg. 1997;23(12):1081-1087. DOI: 10.1111/j.1524-4725.1997.tb00449.x. PMID: 9423959.

14. Gage AA, Guest K, Montes M, et al. Effect of varying freezing and thawing rates in experimental cryosurgery. Cryobiology. 1985;22(2):175-182. DOI: 10.1016/0011-2240(85)90172-7. PMID: 3979092.

15. Kuflik EG. Cryosurgery for skin cancer: 30-year experience and cure rates. Dermatol Surg. 2004;30(2 Pt 2):297-300. DOI: 10.1111/j.1524-4725.2004.30087.x. PMID: 14871226.

16. Kwok CS, Gibbs S, Bennett C, et al. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2012;9:CD001781. DOI: 10.1002/14651858.CD001781.pub3. PMID: 22972052.

17. de Berker D, McGregor JM, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the care of patients with actinic keratoses 2017. Br J Dermatol. 2017;176(1):20-43. DOI: 10.1111/bjd.15107. PMID: 28098380.

18. Kuflik EG, Gage AA. The five-year cure rate achieved by cryosurgery for skin cancer. J Am Acad Dermatol. 1991;24(6 Pt 1):1002-1004. DOI: 10.1016/0190-9622(91)70161-4. PMID: 1869688.

19. Sonnex TS, Dawber RP, Ralfs IG, et al. The hazards of cryotherapy. Br J Dermatol. 1982;107(2):215-217. DOI: 10.1111/j.1365-2133.1982.tb00341.x. PMID: 7104109.

20. Steele K, Shirodaria P, O'Hare M, et al. Monochloroacetic acid and 60% salicylic acid as a treatment for simple plantar warts: effectiveness and mode of action. Br J Dermatol. 1988;118(4):537-543. DOI: 10.1111/j.1365-2133.1988.tb02457.x. PMID: 3377970.

Key Studies

21. National Institute for Health and Care Excellence (NICE). Skin Cancer Prevention. NICE guideline [PH32]. London: NICE; 2016.

22. Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502-518. DOI: 10.1111/bjd.12420. PMID: 23647091.

23. van der Wouden JC, van der Sande R, Kruithof EJ, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2017;5:CD004767. DOI: 10.1002/14651858.CD004767.pub4. PMID: 28513067.

24. Jackson A, Colver G, Dawber R. Cutaneous Cryosurgery: Principles and Clinical Practice. 2nd ed. London: Martin Dunitz; 1996.

25. Hoffmann NE, Bischof JC. The cryobiology of cryosurgical injury. Urology. 2002;60(2 Suppl 1):40-49. DOI: 10.1016/s0090-4295(02)01683-7. PMID: 12206847.

26. Baust JG, Gage AA, Ma H, Zhang CM. Minimally invasive cryosurgery—technological advances. Cryobiology. 1997;34(4):373-384. DOI: 10.1006/cryo.1997.2017. PMID: 9200818.

27. Gage AA. Cryosurgery in the treatment of cancer. Surg Gynecol Obstet. 1992;174(1):73-92. PMID: 1729752.

28. Hoffmann NE, Bischof JC. Cryosurgery of normal and tumor tissue in the dorsal skin flap chamber: Part I—Thermal response. J Biomech Eng. 2001;123(4):301-309. DOI: 10.1115/1.1385838. PMID: 11563755.

29. Clarke DM, Baust JM, Van Buskirk RG, Baust JG. Chemo-cryo combination therapy: an adjunctive model for the treatment of prostate cancer. Cryobiology. 2001;42(4):274-285. DOI: 10.1006/cryo.2001.2333. PMID: 11748935.

30. Ceilley RI, Del Rosso JQ. Current modalities and new advances in the treatment of basal cell carcinoma. Int J Dermatol. 2006;45(5):489-498. DOI: 10.1111/j.1365-4632.2006.02562.x. PMID: 16700779.

31. Kuflik EG. Cryosurgery for cutaneous lesions. Dermatol Clin. 1994;12(4):709-715. PMID: 7805301.

32. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis"). J Am Acad Dermatol. 2000;42(1 Pt 2):11-17. DOI: 10.1067/mjd.2000.103339. PMID: 10607352.

33. Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380(10):935-946. DOI: 10.1056/NEJMoa1811850. PMID: 30855745.

34. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol. 2008;158(5):994-999. DOI: 10.1111/j.1365-2133.2008.08488.x. PMID: 18284390.

35. Thissen MR, Neumann MH, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol. 1999;135(10):1177-1183. DOI: 10.1001/archderm.135.10.1177. PMID: 10522664.

36. Morton CA, Birnie AJ, Eedy DJ. British Association of Dermatologists' guidelines for the management of squamous cell carcinoma in situ (Bowen's disease) 2014. Br J Dermatol. 2014;170(2):245-260. DOI: 10.1111/bjd.12766. PMID: 24313974.

37. Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol. 1995;131(12):1453-1457. PMID: 7492140.

38. Nordin P, Larko O, Stenquist B. Five-year results of curettage-cryosurgery for 100 consecutive auricular non-melanoma skin cancers. J Laryngol Otol. 1999;113(12):1068-1071. DOI: 10.1017/s0022215100146274. PMID: 10767917.

39. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43(9):687-692. DOI: 10.1111/j.1365-4632.2004.02056.x. PMID: 15357754.

40. Bruggink SC, Gussekloo J, Berger MY, et al. Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. CMAJ. 2010;182(15):1624-1630. DOI: 10.1503/cmaj.092194. PMID: 20855477.

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