Guidelines for cryotherapy

Introduction

Cryotherapy is a controlled and targeted destruction of diseased tissue by the application of cold temperature substance. It is used for the treatment of diverse benign lesions and well-circumscribed pre-malignant and malignant tumors.

Status of Cryotherapy in the Present Era

In the present age, despite the advent of several ablative procedures like radiofrequency or laser therapy, cryosurgery continues to occupy a very important position in the therapeutic armamentarium of a dermatologist. It is a very safe, inexpensive, reproducible, repeatable and simple office procedure. It requires a short preparation time, is a sutureless procedure with minimal risk of infection and no anesthesia is usually required. It can be performed at any age, including in old patients with pacemakers in whom electrocautery is contraindicated, those on anticoagulants, patients allergic to anesthetic agents, patients with transmissible conditions such as human immunodeficiency virus (HIV) and hepatitis, during pregnancy and over most of the body sites. It provides high healing rates even in difficult areas, with excellent cosmetic results if performed appropriately. In view of all these advantages, it is regarded as a treatment of choice by many dermatologists for various benign and malignant dermatoses.

Theoretical background: mechanism of cryoablation

Tissue destruction occurs as a result of rapid heat transfer from the tissue causing tissue injury, vascular stasis and occlusion and inflammation.

On spraying the cryogen, there is a rapid transfer of heat from the tissue to the cryogen, with ice formation in the extracellular compartment. The extracellular solutes are concentrated, setting up an osmotic gradient, with movement of fluid extracellularly and concentration of solutes within the cell leading to cell damage. The ice crystals also damage the cell membrane mechanically. Moreover, intracellular ice formation occurs, damaging organelles like mitochondria and endoplasmic reticulum. There is severe vasoconstriction and endothelial damage due to cold temperature leading to platelet aggregation and microthrombi formation, producing ischemic necrosis of the tissue. There is inflammation in response to cell death causing further destruction. ^{[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15]}

There is differential sensitivity of each cell or tissue to cryodamage, with melanocytes and deeper epidermal cell layers being very sensitive and dermal collagen being cryoresistant.

Rationale and scope: The guidelines include information on the apparatus and cryogens required for cryotherapy, pre-operative preparation, various techniques to be adopted in order to achieve good cosmetic results with minimal complications, post-therapy complications that can be encountered and their management, indications for cryotherapy, number of sessions required, interval between sessions and number of freeze thaw cycles for each type of lesion. An approach to minimize side effects and maximize efficacy is suggested. The complications and contraindications of this procedure are also addressed.

Physician qualification : A qualified dermatologist can undertake cryotherapy after receiving adequate training in the field during post-graduation or through recognized fellowships and workshops dedicated to cryotherapy. A 1-day demonstration workshop is adequate to learn this procedure.

Facility: Cryotherapy can be undertaken in a physician′s office procedure room or minor theater with a high degree of aseptic precautions. A fully equipped minor operation theater with good lighting, appropriate minimal sterilization and storage facilities is desirable.

Cryogen

The commonly used cryogens include: ^{[15],[16],[17]}

Cryogens - Boiling point Liquid nitrogen (most commonly used) : -196°C

Nitrous oxide : - 89°C

Solidified CO ₂ (dry ice, CO ₂ snow) : -78°C

Chlorodifluoromethane : -41°C

Dimethyl ether and propane : -24°C, -42°C

Cryosurgery equipment

1. Cryogun/cryogen spray canister: it is a portable, light weight, hand-held device with a controllable trigger to begin and end cooling. ^{[15],[16],[17]}
2. Cryospray nozzle, cryprobes, spray tips, neoprene or polystyrene cones.
3. Cryoprobes: they are available in various shapes and sizes and get attached to the cryogen. They are cooled by the spray of the cryogen.
4. Cryogen storage device: they are metal cylinders/containers that store gaseous cryogens as compressed gas and have an inbuilt internal pressure equalization mechanism e.g., Dewar′s gas container. The cryogen is transferred to the cryogun before the procedure by a siphon or by tilting the container to pour the cryogen into the gun via a funnel. Insulated gloves must be worn while transferring the cryogen. e.g., Brymill cryogenic system.

Methodology of Cryosurgery

Counseling and consent: A written informed consent is obtained from the patient after explaining the procedure, the achievable results, recurrence rate and various complications of the procedure. The consent form should mention the possibility of temporary post-inflammatory blister formation and pigmentation alterations.

History taking and examination: A detailed history of general medical condition, previous treatment received for the condition with results and whether it is a primary or recurrent lesion, is taken. History of sensitivity to cold, cold urticaria, Raynaud′s phenomenon or vascular insufficiency may be recorded. Physical examination to assess the skin type of the patient, lesional characteristics such as size, margin, location, depth, biological behavior and approximation to superficial nerves and previous treatment sites should be undertaken.

Pre-operative preparation: The area to be treated is adequately exposed and cleaned thoroughly with spirit or povidone iodine. Usually, intralesional or topical anesthesia is not required. It may be used for malignant lesions because a longer freeze time required to ablate deeper malignant tissue may produce severe pain. An anxious patient is counseled and an analgesic or antianxiety drug may be administered. The surrounding normal skin may be insulated to prevent spray of surrounding areas. Sites such as the eyes, nares and ears must be protected with goggles, gauze or padding.

Treatment: Different methods of applying the cryogen to the skin lesion include:

Timed spot freeze technique: The cryogen is directly sprayed onto the lesion through an appropriate sized nozzle, which is chosen according to the size of the lesion. The nozzle is held 1 cm from the skin surface and the cryogen is sprayed in the center of the lesion until an ice ball forms that completely encompasses the lesion (confirmed by palpating between the fingers) and the desired margin is reached. For adequate treatment, the lateral spread of freeze should extend at least 2 mm beyond the margin in a benign lesion and 5 mm or more for a malignant lesion. The spraying is continued for an adequate duration (holding time) after which the lesion is allowed to thaw to complete one freeze thaw cycle. Complete thawing is suggested by the disappearance of the frozen-white surface. For larger lesions (> 2 cm in diameter), different parts of the lesion are treated separately with overlapping margins.

Spot freeze can be carried out in two ways:

1. Open spray technique - it is used for large lesions or when light superficial freeze is desired. There are two methods for open spray:
   1. Paint brush method - the lesion is treated by spraying from one side of the lesion and moving up and down across the lesion.
   2. Spiral method - the cryogen is sprayed initially in the center of the lesion and is then moved outward in concentric circles.
2. Confined-spray technique - it is preferred for round, small, discrete lesions or those close to vital structures. In this, the range of spray is limited to a discrete area by the use of neoprene or polystyrene cones.

Use of cryoprobe: An appropriate-sized cryoprobe attached to the cryogun is directly applied to the lesion before spraying the cryogen. A thin layer of vaseline or petrolatum is applied to the probe tip to allow smooth contact with the lesion. While the cooling is occurring, the lesion gets attached to the probe, which should be raised above the surrounding normal skin by few millimeters to prevent damage to the surrounding skin. Once the lesion is frozen, it is allowed to thaw. The probe should be allowed to release spontaneously from the lesion during the thawing process and must not be pulled earlier. In this technique, a longer freezing time is required as compared with the open spray technique.

This technique is preferred in vascular lesions because direct application of the cryoprobe blanches the lesion and reduces the lesional temperature thus increasing the depth of the freeze.

Dipstick method: A cotton bud is dipped into the cryogen (liquid nitrogen slush or dry ice) placed in a disposable container and then applied firmly on the lesion until a halo of ice forms around the bud. The size of the bud should be smaller than the lesion. The depth of freeze can be increased by applying pressure on the lesion. The method has the advantage of not needing a spray or probe equipment and is therefore cheap. However, repeated applications may be necessary to achieve a proper freeze thaw.

Histofreezer: It has been primarily advocated for the treatment of warts. It is a gentler treatment than liquid nitrogen because a higher temperature is achieved, it is less expensive and is easy to store. It is a small unit containing a liquid-gas mixture of dimethyl ether and propane in an aerosol spray can. The mixture is sprayed through a narrow tube to a cotton applicator, which is applied to the wart. The mixture evaporates and freezes the wart. A temperature of -50°C is reached at the cotton tip, which freezes the wart. In a randomized trial comparing liquid nitrogen cryotherapy and histofreezer for the treatment of hand warts, patients cured of warts were 67% and 35% ( P = 0.01) and the number of warts that resolved were 66% and 49% ( P = 0.08) with the two modalities, respectively. ^[1] The treatments were about equally effective in dorsal non-protuberant and small (< 5 mm) warts, but the overall results of liquid nitrogen were better. It is not available in India. Post-treatment care

The patient is explained about the immediate skin reactions that occur post-cryotherapy. There is peripheral erythema occurring immediately to 30 min after therapy, with edema setting in within a few minutes to few hours. There may be blister formation 1-3 days later followed by crusting that lasts for up to 2 weeks. The crust falls off leaving behind a mild pinkish discoloration or erythematous atrophic scar. The patient is asked to apply a mild to moderately potent topical steroid and antibiotic combination. If the blister is large, it may be punctured with a sterile needle or aspirated with its roof left in position as a natural protective film. A non-steroidal anti-inflammatory drug (NSAID) is concomitantly administered. The treated area is best left open, washed gently with soap and water and patted dry.

Indications for cryotherapy

This procedure has been used to treat a wide variety of skin conditions shown in the appendix, e.g. ^{[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49]}

1. Vascular lesions
2. Benign tumors
3. Acne
4. Pigmented lesions
5. Viral infections
6. Inflammatory dermatoses
7. Infectious dermatoses
8. Pre-malignant and malignant tumors

Note: Most of the evidence on the effectiveness of cryosurgery for the above indications comes from uncontrolled trials.

With the advent of several sophisticated ablative procedures like radiofrequency ablation or lasers, the following conditions are recommended as specific indications for cryosurgery:

• Genital warts in HIV-positive patients or during pregnancy. ^[2]
• Hemangiomas/vascular malformations - macular, flat-topped, superficial lesions, exophytic lesions or those with a subcutaneous component (deep or mixed hemangiomas and malformations). ^[3] (Level C evidence).
• Well-defined, superficial non-melanoma skin cancers (basal and squamous cell carcinoma), especially located on the trunk. (Level A evidence).^[4]
• As combination therapy for lesions located on covered sites. E.g., plantar warts in combination with keratolytics, keloids in combination with I/L steroids. ^[5],[6]

In other dermatoses, it may be used as alternate therapy, especially under the following circumstances:

• In old patients with pacemakers in whom electrocautery is contraindicated
• In patients on anticoagulants
• In subjects allergic to anesthetic agents
• Patients with transmissible conditions such as HIV and hepatitis
• For genital lesions during pregnancy
• If other ablative modalities are not available

The list of dermatoses where cryotherapy has been used along with the levels of evidence are listed in the Appendix.

Complications: These are associated with inappropriate patient selection, duration of freezing and number of freeze thaw cycles undertaken. ^[7],[8]

Acute complications

• Local pain - more in the periungual area, temple, plantar areas, eyelids, lips, mucous membranes. Tingling and numbness, especially on the fingers.
• Edema, especially on the eyelids, lips, labia and prepuce, more in infants and the elderly.
• Cryoblister formation.
• Syncope (vasovagal reaction) in anxious patients.
• Headache (migraine type) after the treatment of the head and neck area.

Subacute complications

• Hemorrhagic necrosis.
• Wound infection due to the use of infected cryoprobes or redipping cotton swabs into the cryogen.
• Delayed wound healing after treatment over the extremities.
• Temporary scar hypertrophy.
• Subcutaneous emphysema due to insufflation of the underlying tissue on spraying over broken skin.

Protracted complications

Common

• Hypopigmentation, especially in dark-skinned individuals, which can be minimized by freezing for < 30s.Atrophic scar, which occurs when freezing time is> 30 s.
• Local hypoaesthesia due to nerve damage, especially in areas where the nerves lie superficially, such as the sides of fingers, angle of jaw, post-auricular area, sides of tongue and ulnar fossa of elbow.
• Milia formation.
• Cicatricial alopecia, which can be minimized by freezing for < 30 s.

Uncommon

• Cartilage damage.
• Traumatic neuroma.
• Pyogenic granuloma.
• Fibroxanthoma.

Contraindications to cryotherapy

Absolute

• Blood dyscrasias of unknown origin.
• Cold intolerance.
• Raynaud′s disease.
• Cold urticaria.
• Cryoglobulinemia.
• Lesions in which tissue pathology is required.
• Lesions in areas of compromised circulation.
• Sclerosing basal cell carcinoma (BCC) or recurrent BCC or squamous cell carcinoma (SCC ) located in high-risk areas like the temple or nasolabial folds.

Relative

• Keloidal tendency.
• Collagen vascular diseases.
• Dark-skinned individuals due to the high risk of developing cosmetically inacceptable protracted hypopigmentation.
• Lesions over the nasolabial fold, eyelid margins, ala nasi and hair-bearing areas (high risk of developing alopecia, especially cicatricial alopecia).
• Patients with sensory loss at lesional sites.
• Pyoderma gangrenosum.

Conclusion

Cryotherapy is a simple, safe and inexpensive office procedure for the treatment of various benign, pre-malignant and well-circumscribed malignant tumors. It provides satisfactory cosmetic results with minimal complications if patient selection is proper and if it is undertaken by a trained and experienced dermatologist.