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Historical Background:

The use of cryogenics in medicine is not new ; it dates back to the ancient Egyptians of 2500 Before Christ (B.C.) (Squazzi and Bracco, 1974).They found that the application of cold soothes sites of trauma and reduces inflammation. In the fifth century Before Christ, Hippocrates, recommended hypothermia to reduce edema, hemorrhage, and pain and observed that it had anesthetic properties. These findings were corroborated by the physician surgeon, Baron Dominique Jean Lorry, who was the military surgeon during Napoleon's historic and tragic retreat from Moscow. He noted that the limbs of wounded soldiers could be amputated with a minimum of pain and hemorrhage if the limb was covered with ice or snow before the operation. In 1845 Dr. James Anatt of London pioneered refrigeration analgesia for the treatment of neuralgic rheumatism and for the palliative relief of cancerous tumors in the terminally ill patients. He was able to achieve temperatures of -24 ^oC by employing a brine solution with ice to administer cryotherapy to his patients (Arnott, 1855).

The first use of extremely cold refrigerants for medical disorders is credited to White in 1899. He was a New York city physician, trained in dermatology, with the inborn curiosity and investigative nature so vital to a clinician; he explored the medical application of liquefied gas, which had been discovered more than two decades earlier. Initially he dipped cotton-tipped applicators into liquefied air and successfully treated verruca, nevi, and pre cancerous tumors of the skin (White, 1899).

In 1907 White-house, another New York dermatologist, abandoned the cotton- tip application of liquid air and devised an ingenious method to spray the refrigerant. His technique for treatment of skin cancers has historic importance (Whitehouse, 1907). In the past half-century, cryobiology emerged as a true science, thanks in part to the fundamental contributions of Luyet, (Luyet, 1964) Gehinio, (Luyet and Gehinio, 1940) Smith, (Smith, 1961) and Polge (Polge et al., 1949). Their contributions have increased our knowledge of cellular biological alterations resulting from subzero environments (Zacarian, 1985a).

Cryosurgical Approach to Benign conditions of the skin:

Cryosurgery is reported to be a rational therapeutic modality for a variety of benign and premalignant conditions of the skin. The cryosurgical management of these diseases demands a different philosophy from the clinician than does that of malignant lesions. Specific rules must be kept in mind when dealing with Benign lesions different from that of malignant ones.The overriding rule in treating malignant lesions is cure. This is not necessarily true in Benign lesions, improvement rather than cure may be the primary target in treating benign lesions. The depth of freezing is more superficial and the duration of application of the freeze is much shorter in treating benign lesions than malignant ones. Freeze-thaw times are adequate clinical measures and when coupled with palpation form sufficient parameter of freezing in the vast majority of cases one of the golden rules in treating benign or malignant tumors is that, it is better, when in doubt to under treat rather than overtreat (Zacarian, 1985a).

The reasons for this are, first we may not be concerned with complete cure in many types of Benign lesions second, certain complications can be kept to a minimum, last. The benign nature of the condition allows more time and flexibility in adjusting the treatment regimen. Certain complications in the treatment of cancerous tumors are much less frequent in the treatment of Benign lesions. This is mostly due to the shorter and more superficial freezing technique preoperative anesthesia is rarely necessary in treating Benign lesions. This is in contrast to its essential use in malignancies to lessen the severity of pain of deep freezing (Torre, 1973; Lubritz, 1985).

Basics of the cryobiological effects:

The development of the cryolesion and its subsequent thermal sequences and resulting cryonecrosis depend on a number of important considerations .

1 - The capacitance or boiling temperature of the cryogen,

2 - The probe size or aperture of the refrigerant spray.

3 - The volume and depth of tissue to be frozen.

4 - The osmolality and thermal conductivity of the given tissue.

5 - The cellular and structural composition of the tissue or tumor.

6 - The degree of vascularity and rate of blood flow within the tissue and the velocity of cooling (Gill et al., 1970).

7 - The thermal constant of the human skin (Brodthagen, 1961; Zacarian, and Adham, 1967). Heat transfer and speed of thermal diffusion in the skin depend in part on both the conductivity and the specific heat of skin. Conductivity is the ability of the skin or a given tissue to carry away or transmit the quantity of heat supplied. Specific heat is the ability of skin or a given organ to absorb the quantity of heat supplied (Zacarian, 1985a).

Cellular response to freezing: The fundamental change during freezing is the conversion of the liquid content of the cell and its interspaces into a solid state; namely, ice. This phase change takes place during the period of heat exchange between the living cellular structures and the coolant to which it is suddenly exposed. The more rapid this exchange and the greater the degree of hypothermia, the more deleterious is the effect on living cells. A rapid thawing allows more survival, whereas a slower thaw rate induces a higher cell death ratio (Mazur et al., 1957).

Some of the recognized and documented changes that take place within a cell subjected to freezing are these (Zacarian, 1985a):

1 - Development of extracellular ice formation.

2 - Development of intracellular ice formation.

3 - Abnormal concentration of electrolytes within the cell.

4 - Eventual crystallization of electrolytes.

5 - Cell dehydration leading to cell shrinkage and pyknotic changes.

6 - Thermal shock.

7 - Denaturation of lipoprotein complexes. All of these changes are complex and depend on a number of factors . For example, slow cooling produces large ice crystals, which are not as lethal as the micro crystals that develop with rapid cooling. The duration of the freeze also determines the location and size of ice crystals (Zacarian, 1985a).

A given tissue is not a homogeneous biological unit, and that freezing temperatures are at various thermal gradients. Cells closest to the heat sink experience the most rapid and precipitous drop of temperature, whereas cells and biological structures peripheral and distal to the heat sink undergo freezing at a slower rate. Despite this disparity, the physical alterations that a living cell undergoes when subjected to freezing temperatures is incompatible with life (Meryman, 1956, Meryman, 1960, Love, 1966; Mazur, 1966).

There are distinct differences in cell sensitivity to subzero temperatures. Melanocytes and pigment-bearing cells, for example, are extremely sensitive to freezing (Gage et al., 1979). Gage and Co-workers noted that destruction of melanocytes occurred at the range of -4 to -7°C, in contrast to squamous cells, which resisted injury at -20°C. Dermal connective tissue and fibroblasts, on the other hand, are quite resistant to cold injury, even at temperatures in the vicinity of -30 to-35°C (Shephard, 1979).

What temperatures are lethal for cells?. It was found that the optimal temperature for achieving effective cryonecrosis of malignant tumor of the skin is - 50°C (Neel et al., 1971, Zacarian, 1973, Neel and Ketchum, 1977 ; Gage, 1979). It has already been established that, at this temperature all electrolytes within a mammalian cell are crystallized and no longer viable. Utilizing electron microscopy studies of in vivo experiments, Uyeda noted that with double freeze-thaw cycles the degree of cryonecrosis was much more pronounced than with a single freeze-thaw ones. Similar conclusions were reached by Gage (Gage, 1978, Uyeda et al., 1978). Zacarian noted that the degree and depth of cryonecrosis with double freeze-thaw cycles were more profound and extensive than those of a single freeze-thaw cycle (Zacarian, 1977).

Vascular response to freezing temperatures :

A well developed integrity of circulation within an intact vasculature is synonymous with life itself. The micro vessels (arterioles, venules, and capillaries) are terminal vascular components of the circulatory system comprising over 90 % of the blood vessels in a mammalian organism. Experimental evidence supports the view that about 63 % of capillary circulation ceases between +11 and +3°C, whereas 35 % to 40 % of blood flow ceases in the arterioles and venules (Rinfert, 1962).

Cryogenic injury to a tissue leads to vascular stasis and inevitable tissue anoxia with resulting ischemic necrosis (Kreyberg, 1957). The immediate response to freezing of the micro vessels was vasoconstriction. Within 45 minutes, marked vasodilatation was observed after freezing (Zacarian et al., 1970). After the initial vasoconstriction, the micro vessels underwent a sustained vasodilatation, and showers of emboli were seen rapidly passing through the damaged arterioles, venules, and capillaries. Once thrombi became permanently lodged, circulation ceased and rendered that area of the frozen tissues ischemically necrotic (Mundt, 1969; Zacarian, 1970). After refreezing that area 30 to 40 minutes later, all circulation ceased in that segment and never returned . The tissues were examined daily and nothing was observed but progressive necrosis. This damage to the microvessels appeared even at the nominal temperatures of -15 to -20°C. With a deeper freeze, pathogenesis was accelerated with the same pathological alterations (Zacarian, 1985a).

Cryogens used in Cryosurgery:

Sufficient cold for cryosurgery, can be produced in many ways; electro- mechanically, by refrigeration, by lowering the pressure of a gas (Joule-Thompson effect), and by direct or indirect application of a solid or liquid refrigerant stored at low temperature (Bowen and Towle, 1907). Many cryogens are known but there are four in common use; Carbon dioxide, Nitrous oxide, Liquid nitrogen, and Fluorocarbons (Lubritz, 1987).

(A).Liquid nitrogen : Liquid nitrogen is the cryogen of choice for dermatological cryosurgery and the only cryogen advocated for treatment of malignant skin lesions. Liquid nitrogen requires a storage container. Vacuum-insulated Dewars are available in many sizes. The most popular Dewars for office use have a capacity range of 15 to 35 liters and a holding time of 60 to 90 days. These are refilled by many welding supply companies at 3 week to 6 week intervals. Withdrawal devices are necessary to transfer the liquid nitrogen from the storage Dewar flask to the cryosurgical instruments . Liquid nitrogen is considered the most suitable cryogen for dermatological cryosurgery as it is inexpensive, non explosive, generally available as well as its boiling temperature is at -196°C. So it is the most powerful cryogen available for cryosurgery (Zacarian, 1985a)

(B).Carbon dioxide : Carbon dioxide can be obtained in blocks or produced as snow by carbon dioxide cylinders. Pencils can be made either from the solid chunks or snow which can be applied directly on the target tissue. Solid carbon dioxide may be crushed and mixed with acetone and / or alcohol for slush application. However, since carbon dioxide has minimum temperatures of only -79°C, it is limited in its applications to shallow, benign lesions (Torre, 1977).

(C).Nitrous oxide : Nitrous oxide is stored easily. It reaches a minimum temperature of -89 C. Although it works well in a cryoprobe system, it is difficult to use in spray technique. Difficulty arising from the fact that, if the fine droplets of liquid nitrous oxide are released in an open air situations the droplets instead of vaporizing to gas, crystallize into solid nitrous oxide particles, that lie on the surface or fly in all directions. It also has a limited depth of penetration (Torre, 1977).

(D).Fluorocarbons liquid (Freon) : Fluorocarbons liquid can be used in a spray technique. These are available commercially in two forms; one providing a surface temperature of -30°C, the other -60°C. These cryogens are particularly useful for treating broad areas. Difficulties in delivering the cryogen on the skin as freon tend to pool and potential cardiac toxicity limit its usefulness (Harris, 1973; Nicholas, 1974).

Cryosurgical Techniques :

Cryosurgery can be applied either by surface cryosurgery or intralesional technique:

A. Surface cryosurgery:

(1)-Cotton Swab Technique : When using the cotton-tipped applicator method, large swabs create large frozen surfaces, generally overriding the limits of the area intended for treatment. Although small swabs produce smaller frozen areas, their "reservoir" capacity is so limited that multiple applications are usually necessary (Claude, 1986).

The "hard tail" dip-stick is made out of a standard large cotton-tipped applicator. At its end, a tiny amount of cotton is pinched between the index finger and thumb and strongly twisted in order to obtain the so-called "hard tail". The distal part of the tail is cut down so that the total tail does not exceed 5 mm. The degree of hardness of the tail is a factor that must be stressed. If the tail is not hard enough, it cannot easily remain in contact with the lesion and is useless. Therefore, one should not pull a tiny amount of cotton but only pinch it before twisting it strongly. liquid nitrogen is slowly released at the pointed end of the swab, producing a highly accurate freezing effect. After the lesion has thawed, further applications can be done during the same visit (Claude, 1986).

Indications for this method included a wide variety of benign skin lesions such as common warts, condyloma acuminata, seborrheic keratoses, and molluscum contagiosum. The use of the hard tail was especially rewarding in small -5 mm in diameter and less- or ill-defined lesions such as periungual warts, filiform warts, and tiny seborrheic keratoses including dermatosis papulosa nigra. Generally, as the Depth in this technique is superficial it should be applied only for superficial lesions (Zacarian, 1985a).

(2).Spray Technique : Torre pioneered the development of spray method into a successful modality. It can be employed for lesions with irregular surfaces. Characteristically, it produces a depth of freeze more superficial than its lateral spread. In this process the cryogen is applied from an open spray tip directly onto the target site. The spray technique is performed as follows; Select a needle size that applies the spray within the borders of the lesion when started at the center. This is a problem only with lesions less than 0.5 cm in diameter. A needle tip opening that is too large in these instances does not permit fine control. Place the spray nozzle at the center of the lesion. Start at a distance of approximately 1 cm from spray tip to target site. The tip may then be adjusted toward or away from the target area as needed for control of the procedure. Freeze, for a desired freeze time or for an expected thaw time. The feeling for this is based primarily on experience and must be acquired. If another cycle is desired ,it must be performed immediately after a complete thaw of the frozen site. It must be stated here that multiple freeze-thaw cycles do not carry the same importance in treating benign and premalignant lesions as in the case with malignancies. Most benign cases require only one cycle if adequate freezing has been accomplished in the first cycle (Lubritz, 1985).

There are three basic spray patterns. A spiral pattern is gradually enlarging circles of spray. The spray is started in the center of the lesion and carried in an ever-widening spiral. This method is suitable for round lesions such as actinic keratoses. The paint brush pattern is started at the lateral point of the lesion and carried back and forth over the entire extent of the lesion either horizontally or vertically. The mid way zone pattern occurs from concentration of the spray in a circle midway between the center and the periphery of the lesion. This pattern is suitable for large lesions (Lubritz, 1978).

(3).Cryoprobe technique : Zacarian has made fundamental and important contribution to the development of this technique. This technique can be used on lesions with regular surfaces. It is slower than spray technique. A probe results in a deeper depth of freeze than does the spray. The probe surface is cooled by previous immersion in the cryogen (liquid nitrogen or nitrous oxide) or by circulating the cryogen either inside or through it. A heat sink is thus created as heat is transferred from the treatment site to the probe (Zacarian and Adham, 1966; Zacarian, 1969). The cryoprobe technique is done as follows : Selection of a probe type and size suitable to the lesion to be treated . It is best to pre-cool the probe before applying it to the surface of the lesion. This is particularly helpful for wet or mucous membrane lesions, since it helps to prevent the tip from adhering to the site of application. Apply the probe tip firmly to the target site . Pressure in varying degrees can influence the depth of the freeze. Measure adequacy of the freeze by extent of the frozen rim of normal tissues. Allow the probe to thaw sufficiently before removing it from the treatment site. A repeat cycle, if needed, should be commenced after allowing complete thaw of the lesion (Zacarian, 1985).

B. Intralesional Cryosurgery Technique :

This is a new method of applying cryogen in depth to get more effectiveness and avoiding many of the disadvantages of the known techniques. A needle was introduced into the skin from one point to run through the deeper tissue of the lesion and appearing from another point again to the surface. A cryogen was passed through one end of the needle to come out through the other end to the external atmosphere. An ice cylinder was formed around the embedded part of the needle in the deeper tissues. New varieties of needles were invented to facilitate more efficacy in depth. The needles were angulated, curved, and hook shaped. The process was very practical and effective to eradicate 85 % of epidermal lesions from the first session (Weshahy, 1987).

Monitoring the cryolesion :

Methods used for estimating the depth of the freeze includes clinical and instrumental methods. The clinical Methods include; palpation, measurement of the lateral spread of freezing and measurement of thaw time. The instrumentation methods include; Tissue temperature measurement and measurement of electrical resistance or impedance (Zacarian, 1985a). Clinical depth-dose measurements are based on the physics of ice ball formation. Because heat is withdrawn from the tissue, an ice ball forms, spreading downwards as well as laterally. By measuring the lateral spread of freeze on the surface, we can estimate the depth of the frozen tissue as the depth of the tissue ice ball. Depth of freeze roughly equals the lateral spread when using the cryoprobe technique and half that lateral spread in cryospray technique (Torre, 1986). Freezing time is generally not used as an actual measure for the depth of the freeze because it is affected by too many variables. for instance, instruments from different manufacturers vary the freezing time as does the size of the spray nozzle or probe (Lubritz, 1987). Thaw time is an important parameter used to judge the adequacy of freeze. There are two types of thaw times, the total thaw time and the halo thaw time. The total thaw time is defined as " the elapsed time from stopping application of the spray or probe until the entire lesion is thawed ". This end point is detected by the disappearance of the white frosted appearance on the lesion's surface and re-softening of the tissue on palpation.

The thaw time is a retrospective measure and cannot be altered after the freezing procedure has occurred. The halo thaw time is utilized for malignant lesions and defined as the elapsed time from stopping application of the spray or probe until the frozen rim of normal tissue (halo) is thawed. The halo thaw time should be at least 60 seconds. With open spray technique, the halo thaw time is double the freezing time while with closed cone spray technique, it is four times the freezing time (lubritz, 1987). The temperature measurement is obtained by the use of a thermocouple pyrometer system. The thermocouple is hardly, if ever, used in benign and premalignant lesions. This is in contrast to its essential use in malignancies. It enables the surgeon to measure the temperature at or below the base of the lesion (Zacarian, 1985).

It is important to determine the depth of the lesion, so that the thermocouple needle is properly placed. This can be determined by inspection, palpation, removal of some tumor mass or examination of a biopsy specimen. A thermocouple needle is inserted from a point lateral to the tumor and at an angle of approximately 30°. So, that point comes to lie at the base of the tumor. Adequacy of freezing may also be quantitated by the electrical resistance of the tissue being frozen. This is attributed to, freezing of the water content and electrolytes of a living cell that diminish its electrical conductivity in direct relationship to specific temperatures. When all of the cell water content is frozen and its electrolytes are crystallized - a state referred to as eutectic point - , the cell is no longer viable and it ceases to conduct electricity and electrical resistance has reached its maximum (Fourcade, 1974).

The tissue resistance measuring devices have several advantages over thermocouple pyrometer systems. Thin, inexpensive electrodes Such as "hypodermic needles" can be used instead of the expensive, fragile tipped thermocouple electrodes. Many areas of a tumor can be monitored with a single electrode, whereas a single area can be monitored by a thermocouple needle. Thermocouple-Pyrometer and tissue resistance measuring systems can be used simultaneously and results can be compared (Zacarian, 1985a ).

Complications Of Cryosurgery:

As with any other therapeutic regimen or physical modality, cryosurgery presents a number of complications worthy of consideration. They may be classified according to the time of occurrence to immediate, delayed, prolonged or permanent complications.

Immediate complications includes; pain, headache, insufflation of subcutaneous tissue, intradermal hemorrhage, edema, syncope and vesiculo-bullous formation. Delayed complications include; infection, febrile systemic reaction, hemorrhage, pyogenic granuloma and pseudo-epitheliomatous hyperplasia. Prolonged complications include; hyperpigmentation, development of milia, hypertrophic scars and neuropathy. Permanent complications include; hypopigmentation, ectropion, and notching of the eyelids, tenting or notching of the vermilion border of the upper lip and alopecia of hair bearing sites (Zacarian, 1985b).

Burning type of pain initiates the natural history of the cryosurgical lesion. Pain usually intensifies at the thaw and may last from a few seconds to several minutes. The pain is usually of short duration because of the self anaesthetizing effect of the freeze. Pain is most intense on the fingers, toes, plantar surfaces, eyelids and lips. Deeper freezing produces more intense pain, increasing the likelihood of vasovagal attack. When thawing is complete, pain usually ceases and does not return (Elton, 1985). Insufflation of the subcutaneous tissue is a rare complication and occurs only with spray techniques. The gaseous portion of the liquid enters the open pathway between the skin and the subcutaneous tissues and burrows its way through. The entry site may be a biopsy site or an eroded, ulcerated neoplastic growth (Zacarian, 1985 b).

Edema following cryosurgery is inevitable. The degree of edema not only depend on the degree and intensity of the freeze but also on the anatomical site and the patient's individual reaction to cold. The severest degree of edema is noted at the periorbital area "Very loose areolar tissue" (Zacarian, 1985 b).

Syncope has been reported after cryosurgery. Its exact cause is not well known but it may be due to fear, iatrogenic factors or histamine shock (McMeekin and Moschella, 1979; Elton, 1983).

Vesiculo-bullous formation is common after cryosurgery. Bullae commonly occur after few hours and in many cases they may be hemorrhagic. The development of bullae usually indicates that the tissue damage is minimal. Blister may not develop with very deep freeze (Zacarian, 1985 b).

Hyperpigmentation after cryosurgery is not uncommon . Fortunately, it is transient lasting for a few month or at most a year and promptly resolves (Zacarian, 1985 a).

Milia appear after cryosurgery when freezing is intense. So, it is more common with the closed cone spray technique than with open spray or probe technique (Zacarian, 1985 b).

Hypertrophic scars occasionally appear within 4 to 6 weeks after freezing. Keloids are never reported after cryosurgery. The most common sites for appearance are, the ala nasi, tip of nose, mid-forehead and the back. Spontaneous involution is the rule (Zacarian, 1985 b).

Neuropathy after cryosurgery is a rare but serious complication. It may persist for months or even a year or more. Nerve tissues are very sensitive to cold injury but fortunately the neural sheath is reasonably resistant. Nerves that lie superficially e.g. the anterior aspect of tragus, post auricular area, cubital fossa of the elbow are critical sites (Finelli, 1975; Millns, Fenske and Pierce, 1980).

Hypopigmentation is an inevitable complication after cryosurgery. Melanocytes are extremely sensitive to freezing. Destruction occurs in the range of 4 to 7°C. The degree of hypopigmentation varies from patient to patient. The darker the person, the more prominent the hypopigmentation. A double freeze-thaw cycle produces, as expected, a greater degree of hypopigmentation than does a single freeze. Improvement over months has been observed and complete repigmentation has been recorded (Zacarian, 1985 b).

References

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