General Considerations

Advantages of Cryotherapy (Cryosurgery)

Disadvantages of Cryosurgery

Agents Used for Cryosurgery

There are three basic methods of cryosurgery (Table 14-1).

TABLE 14-1 Cryogenic Agents

Nitrous oxide is quite unstable, and once it is released into the probe, it immediately breaks down to molecular nitrogen and oxygen. The physical characteristics of the nitrous oxide gas enable the cryotip’s temperature to be easily lowered to its boiling point of –89° C. With carbon dioxide, the tip is not as cold, and it will take slightly longer to achieve a quality freeze (–78.5° C).

Nitrous oxide comes in a closed gas cylinder (blue tank, versus brown for carbon dioxide and green for oxygen). The hand-held cryogun, which is connected to the tank with tubing, is structured differently from the liquid nitrogen guns. It is designed to allow a controlled, rapid expansion of nitrous oxide gas within the cryoprobe tip, lowering its temperature to –89° C. The storage tanks preserve nitrous oxide virtually “forever” by keeping the gas under pressure with no port for evaporation (except for cryogun activation). The tanks are moved from storage to use on small carts. The cryoprobes (tips) come in numerous shapes and sizes to match the lesion to be treated. The rounded, pointed, and slanted flat tips are popular for dermatologic applications (Fig. 14-1). The hemorrhoid tip is rarely, if ever, used for hemorrhoids, but its shape allows use for multiple dermatologic lesions. The flat and slightly conical 19- and 25-mm tips that are used for cryosurgery of the cervix can also be used for dermatologic applications.

Figure 14-1 Sample of varying shapes of cryoprobe tips. Most come in variable sizes. A, Hemorrhoid tip. B, Slanted flat tip. C, Pointed tip. D, Flat cervical tip. E, Slight conical cervical tip.

Because nitrous oxide does not achieve a probe temperature as low as liquid nitrogen (–89° C versus –196° C), it is significantly slower at freezing tissue. This is especially important when treating multiple lesions. Both nitrous oxide and liquid nitrogen are effective for treating malignancies. Overlapping treatment areas for larger lesions using large probes ensures efficacy. Nitrous oxide units have an active defrost mode that rapidly frees the cryotip from frozen tissue.

CryoPen is a closed, self-contained refrigerant system. It uses an internal cryogen that is cooled in a free-standing unit to −95° C. It eliminates the handling of cryogen gases and liquids. CryoPen reusable tips are available in 3-, 5-, 7-, and 10-mm sizes. These are applied directly to the lesion and maintained in place until the clinical end point has been reached.

Liquid nitrogen is the coldest cryogen, effecting a rapid, deep freeze (boiling point –196° C). A large storage container (Dewar) is needed. Newer Dewars can store the liquid nitrogen for up to 1 year. Liquid nitrogen is relatively inexpensive, but if not used it will evaporate. Liquid nitrogen may be applied to the lesion directly using cotton-tipped applicators or sprayed using a thermos-type unit (Brymill CRY-AC and CRY-AC-3 [Brymill Cryogenic Systems, Ellington, Conn], or Wallach UltraFreeze [Wallach Surgical Devices, Orange, Conn]). The various apertures of the spray tips allow a variable amount of gas to cover a lesion, allowing control over the extent of freezing. A reusable plastic shield is available to limit gas spread. These spray units allow efficient and rapid treatment of multiple lesions in a single office visit. Additional probes are available that allow the thermos to be used as a closed system, but there is no active defrost. Subsequently, the tip may “stick” to the tissue for a significant length of time before it thaws and detaches.

Canister refrigerants are the least expensive agents used for cryosurgery. They come prepackaged in small hand-held canisters the size of a soda can, making them portable for use in nursing homes, satellite clinics, and multiple examination rooms. They have a very long shelf life. Unfortunately, they do not achieve tissue temperatures low enough to treat very many lesions. These agents are not indicated for malignancies, deep lesions, or large lesions. Trifluoroethane/pentafluoroethane/tetrafluoroethane (Verruca-Freeze [CryoSurgery, Nashville, Tenn; Medi-Frig [Ellman International, Oceanside, NY]) is a nonflammable compressed gas that freezes tissue on vaporization (boiling point −47° C). Dimethyl ether/propane/isobutane (Histofreezer [OraSure Technologies, Bethlehem, Penn]) also comes in a canister but is not as cold (−25° C) and is flammable.

Over-the-counter skin refrigerants were approved for use by the U.S. Food and Drug Administration in 2003. Several products are available, including Dr. Scholl’s Freeze Away, Wartner Plantar Wart Removal System, and Compound W Freeze Off. The first two products contain dimethyl ether and propane. Wartner’s product also adds isobutane to these. Although the manufacturers state that temperatures as low as −57° C are achieved on skin application, such low temperatures were not realized in a recent study. There is significant concern regarding their ability to create local tissue necrosis because of their inability to reach low temperatures rapidly enough to achieve clinical effect. In contrast to other physician-applied options, these over-the-counter products are also dangerous because they are extremely flammable.

Tissue Effects: Principles for Treatment

It is important to recognize that at −2.2° C, cells begin to freeze. At −5° C, cells will supercool, but they recover. Tissue destruction begins only when the temperature is between −10° C and −20° C. A deeper freeze with temperatures between −40° C and −50° C ensures that malignant cells are completely destroyed.

The size of the ice ball that forms around the lesion provides a good estimate of the depth of the freeze. The lethal zone (tissue temperature less than −20° C) is 2 to 3 mm inside the outer margin of the ice ball (Fig. 14-2). This is especially crucial to remember in cases of premalignant or malignant lesions, which are deeper in the skin. The size of the ice ball beyond the lesion is the most important criterion in determining how long to freeze. Factors requiring prolonged freeze time include low tank pressure, increased tissue vascularity, excessive overlying keratin (needs to be removed or moistened), and poor tip-to-lesion contact. The use of different systems (e.g., nitrous oxide, liquid nitrogen, carbon dioxide, canister gases) dramatically affects the rapidity and depth of freeze. Likewise, the method of applying liquid nitrogen (with the cotton-tipped applicator or in a spray fashion) affects freezing parameters. Once an ice ball of the desired size has been obtained, it is just as important to observe the time it takes for the area to thaw from the outer edge of the ice ball to the lesion edge (“halo thaw time”) and the time for all the tissue to thaw (total thaw time; Box 14-1). A brief freeze can turn tissue white, providing the ice ball desired; however, if it remains frozen only momentarily, it will have little effect.

Figure 14-2 Nitrous oxide full-thickness destruction freeze technique (malignant lesions). Note that the outer supercooled area will recover. Monitoring thaw times for both malignant and benign lesions is extremely important (see Box 14-1).

Freeze times should be adjusted according to patient sensitivity, type and size of the lesion, presence of malignancy, and lesion vascularity. Table 14-2 shows the variations with nitrous oxide alone, and Table 14-3 shows those with liquid nitrogen. Age, vascular flow, amount of pigment, depth of lesion, amount of keratin, location on the body, and cell type of the lesion all affect the amount of freezing required to destroy pathologic tissue. Adjust your freeze times accordingly. Applying pressure to the lesion with the fixed probes will increase the depth of freeze. Vascular lesions will require longer freezing times, and pressure from the probe should be applied to squeeze as much blood as possible out of the lesion before freezing. Any active bleeding from a prior shave or curettement will need to be controlled first.

TABLE 14-2 Freeze Time Guidelines for Nitrous Oxide Technique

* Freeze times are approximate guidelines and should be adjusted to the size of the ice ball and the thaw time, which are far more important than the freeze time alone. Because nitrous oxide is slower and more controlled, freeze times are more reliable than with liquid nitrogen.

† Freeze-thaw-refreeze.

TABLE 14-3 Freeze Time Guidelines for Liquid Nitrogen Open-Spray Technique

For benign lesions, a single freeze/thaw cycle is sufficient. The ice ball should extend 2 to 3 mm beyond most lesion margins. Resistant lesions such as warts often require a freeze/thaw/freeze cycle. Complete thaw times should be 2 to 3 minutes for larger lesions.

For malignant or premalignant lesions, a freeze/thaw/freeze cycle is recommended. The ice ball should extend 5 mm beyond the lesion margin each time the tissue is frozen. The second freeze is usually quicker and less painful.

Dry, keratinized tissue will not freeze easily and insulates the lesion underneath from freezing. Remove as much keratin as possible before freezing, especially when using nitrous oxide, carbon dioxide, or the canister agents.

With the nitrous oxide cryotips, once the tip is “frozen” and fixed to the skin, the probe can be pulled back, tenting up the skin, to reduce the depth of freeze, thereby sparing deeper critical structures (such as nerves) from exposure to freezing (Fig. 14-3).

Figure 14-3 With nitrous oxide, once the cryotip is frozen to the skin, the probe can be retracted to avoid freezing nontarget underlying structures.

Bandages are not necessary unless the lesion is continually irritated (i.e., by clothing), develops a large blister, or develops a serous discharge.

Post-Treatment Physiologic Effects

Erythema and hyperemia are immediate responses to effective freezing. Edema and exudation (blister formation) peak within 24 to 48 hours and usually subside after 72 hours (Fig. 14-4). Blood may accumulate under the blister, making it appear black (Fig. 14-5). The extracellular collagen structures are more resistant to freezing than the cells themselves. Crust formation begins, and this crust will slowly contract over the next several days. Reepithelialization occurs from the outer margin inward. Fibroblasts lay down minimal new collagen along the preserved, well-formed collagen matrix, resulting in a lack of scar formation. If the collagen matrix has been destroyed by excessive cryoinjury, fibroblasts will produce collagen randomly, leading to scar formation (Fig. 14-6). Cartilage (e.g., in the ear) is preserved.

Figure 14-4 A, A 10-cm hypertrophic scar over upper abdomen. B, Application of nitrous oxide probe. C, Appearance immediately after thawing. D, Blister formation at 5 hours. E, Ruptured blister at 4 days. F, Appearance at 11 days. G, Final appearance after a second cryotherapy treatment several months later; the small residual scar resolved after the third focal treatment.

Figure 14-5 Appearance of a hemorrhagic bulb after cryotherapy of a plantar wart.

Figure 14-6 Excessive scarring (rare) after cryosurgery of verrucous lesion over first metatarsophalangeal joint of the large toe on the left foot.

If the patient or physician desires, the treated lesion can be surgically débrided in 24 to 48 hours. During this time, the dermis and epidermis separate, lifting the lesion to the top of the blister. Removal of the prepared lesion with iris scissors is painless. After 72 hours, however, the lesion may stick like a graft and may bleed on attempts at removal. If completely left alone, the lesion will eventually slough spontaneously. (Surgical débridement 1 or 2 days after freezing effectively removes the lesion and satisfies some patients sooner. However, many patients are quite happy to avoid the early return visit and are willing to wait to see how much of the lesion sloughs before returning for another treatment.) A disadvantage of this technique is that a second office visit is needed for the 24- to 48-hour débridement procedure, and the serous discharge without the intact blister can be quite copious depending on the size of the lesion.

The healed cryolesion is soft, with minimal to no scarring. This allows erections if penile lesions have been frozen. Pigment is often decreased, and hair and sweat glands may be destroyed in the area of freezing. It is best to caution the patient in advance that although the area that was frozen is unlikely to develop much of a scar, the skin is often lighter. The inflammatory response may result in the development of a transient halo of hyperpigmentation. This will usually clear completely over several months.