MILLENIUM PAPER
History of Dermatologic Cryosurgery
Emanuel G. Kuflik, MD,* Andrew A. Gage, MD,^† Ronald R. Lubritz, MD,^‡ and Gloria F. Graham, MD^§

DERMATOLOGIC CRYOSURGERY began about 100 years ago and has evolved into a method that is used frequently, to one degree or another, by all dermatologists.¹ As with all technologies, the then-new therapy depended on earlier experimental work and clinical observations. Over the years the progress made has been based on the development of new cryogenic agents, new instrumentation to use them in the treatment of skin disease, laboratory research, and clinical experience. This has given cryosurgery a place as a valuable and effective modality in dermatologic surgery.²

Cryosurgery is a versatile method that is used for many benign, premalignant, and malignant skin lesions, either as a primary or as an alternate form of treatment.³ Treatment reduces the temperature of the skin to subzero temperatures, thereby producing localized destruction of tissue.⁴ Healing of the wound occurs by second intention.

The word cryotherapy is often used interchangeably with cryosurgery, although cryosurgery, cryogenic surgery, cryoablation, or cryocoagulation are more accurate descriptions of modern techniques of freezing tissue to achieve a specific therapeutic response. The origin of the term cryotherapy has been attributed to Professor Bordos in 1912 in association with his freezing apparatus and to Giraudeau in 1928. In 1930 Lortat-Jacobs and Solente⁵ published the monograph “La Cryotherapie,” which described diverse ways in which cold or freezing temperatures were used in medicine, especially in dermatology and gynecology. It was also used in the title of a report by Karp et al.⁶ in 1939 on the treatment of acne by a paste made from ground solid carbon dioxide (CO₂), acetone, and precipitated sulfur, which was applied directly to the facial skin in order to achieve superficial exfoliation of the epidermis.

Background

 

The deleterious effects of severe cold on tissue and the benefits from the use of cold as therapy have been known for several thousand years. Tissue damage from cold climatic conditions was described in ancient manuscripts. This may have led to the well-documented use of cold water and ice applications for diverse illnesses and injuries in ancient times, and these uses continued for centuries. Anesthesia by cooling was also known; tissue cooling by surface application of snow and ice was used to facilitate amputation in soldiers in Napoleon's Grand Army.^7–9

In the mid-1800s, James Arnott, an English physician, described the benefits of local applications of cold in a wide variety of conditions, including erysipelas, other cutaneous and general disorders, and cancer. Cancers in accessible sites, such as the breast and uterine cervix, were treated by irrigation with a cold solution, resulting in diminution of the tumor, reduction in drainage, and amelioration of pain. He used salt solutions containing crushed ice in local applications at about -8°C to -12°C to various body surfaces to freeze the tissue. His contributions to the treatment of cancer by freezing are recognized as the beginnings of cryosurgery, although it was the anesthetic effects that attracted the most attention in those years.^10–12 But further development had to await the availability of agents capable of producing much colder temperatures.

In the latter part of the 17th century, scientists observed that atmospheric gases warm when compressed and cool when expanded. Using these principles, Olszenski first liquified air in 1885, which was followed shortly afterward by the commercial liquefaction of air by von Linde. Using this type of process over the next few years, all of the so-called permanent gases (oxygen, nitrogen, hydrogen) were liquefied. The English scientist James Dewar developed a vacuum flask to store fluids. The term “cryogenics” was coined during these years by the Dutch physicist Kamerlingh Omnes, who liquified helium in 1908. These developments permitted the use of cold agents in therapy to enter a new phase because the freezing of discrete lesions became practical.

New York, Cradle of Cryosurgery

Dermatologic cryosurgery began in New York City at the suggestion of Professor Charles E. Tripler, who had the capability of making liquified air in 1893, and urged its trial use in therapeutics, stating that “The cold you doctors have made use of is hot compared with air at 312°F below zero.”¹³ The initial therapeutic uses were for the treatment of skin disease, and in 1899 Dr. A. Campbell White,¹³ of New York, reported using it to treat nevi, warts, varicose leg ulcers, chancroids, boils, carbuncles, herpes zoster, and epitheliomas. He applied liquid air in the form of a spray or by means of a swab dipped into the fluid. A few years later, in 1907, Whitehouse¹⁴ described the use of a spray bottle of liquid air, although he found the use of this technique difficult and stopped using it in favor of a cotton swab. His experience included 15 cases of epitheliomas. Bowen and Towle¹⁵ concluded that liquified air was an excellent therapeutic agent, although impractical because of difficulty in obtaining it. Gold's¹⁶ report of 1910 focused on its use in early epithelioma, lupus erythematosus, vascular nevi, and verrucae. Nevertheless, little mention is made of the use of liquid air after this.

At the same time, the use of CO₂ snow (-78.5°C) was favored by Dr. William Pusey, of Chicago, even though it was substantially warmer than liquid air (about -180°C). The CO₂ was held in the liquified state by a pressure of about 800 psi. When it was released into the air, the decrease in pressure caused freezing and formation of a white snow that was collected in a chamois (leather) bag. The solid was then compressed into appropriate shapes, or sticks, for application onto the skin. The depth of freezing produced by this technique was about 1–2 mm with a skin contact time of 10–30 seconds.¹⁷ The various techniques of forming CO₂ sticks, such as hammering the snow into molds, were described in Low's book published in 1911.¹⁸ Solid CO₂ was the most popular cryogenic agent in the early 1900s, and efforts were made to devise instruments to facilitate its use, such as copper tips or probes connected to a CO₂ source or frigid air forced under pressure through a tube packed with solid CO₂.^5,19,20 While these instruments offered little advantage over the use of the single stick of solid CO₂, they served as prototypes for the CO₂ cartridges available in the 1970s.²¹

In the 1920s, liquid oxygen (-182.9°C) became commercially available but achieved only limited use in the treatment of skin disease; medical reports were relatively few in number because safety considerations related to fire precluded its general use. Irvine and Turnacliff²² reported on its use for warts, lichen planus, and to ameliorate the vesiculation of herpes zoster or contact dermatitis. They emphasized that the use of liquid oxygen as a spray removed the need for pressure in freezing a skin lesion, thereby reducing pain. However, in a discussion of the article Pusey pointed out that pressure was an advantage in that it improved the depth of the effect. In 1948 Kile and Welsh²³ wrote one of the last reports on liquid oxygen.

Following World War II, cryogenic fluids, especially oxygen and nitrogen, became readily commercially available. Their use was rapidly adopted in biology and medicine for various purposes. Liquid nitrogen (-195.8°C), which does not support combustion, was introduced into clinical practice in 1950 by Allington.²⁴ He described the technique of using cotton swabs dipped in liquid nitrogen for the treatment of skin diseases, including warts, keratoses, leukoplakia, hemangiomas, and keloids. Between 1950 and 1960 this technique was used for diverse skin lesions, including some neoplasms.^25,26

This period also saw refrigerants applied by spray come back into use. Kurtin²⁷ used a spray of ethyl chloride as an anesthetic agent during dermabrasion. However, experimental and clinical studies with ethyl chloride and the fluorinated hydrocarbon compounds showed that the agents did not produce freezing more than 1–2 mm in depth.^28–30 Therefore their principal usefulness was an anesthetic agent for superficial surgery.

Thus the choice for dermatologic cryosurgery was between solidified CO₂ sticks and liquid nitrogen applied with saturated cotton tip applicators. In 1960 Hall³¹ sought to determine which technique would provide better results. Brodthagen's³² experiments investigated the depth of freezing and its relationship to the pressure of application. Even with the use of pressure on the CO₂ stick, the depth of destruction was less than 2 mm. Heat exchange was poorer with CO₂ than with liquid nitrogen because it did not provide as low a temperature.

The limitations of the liquid nitrogen-soaked cotton applicator were defined in a report in 1961 by Grimmett,³³ who studied microscopically the depth of destruction by biopsy several days after freezing. The limited freezing capability with the swab technique is not surprising; the thermal mass of a nitrogen-soaked swab is limited, and the heat exchange between the swab and the tissue is poor. Although used for different skin lesions, cryosurgery was still a rather unimportant therapeutic modality because the freezing capability of cryogenic agents applied topically was limited.

In the 1960s, Zacarian and Adham^34,35 attempted to achieve greater tissue depth penetration through the use of solid copper cylinder discs that were cooled by immersion in liquid nitrogen prior to application on the skin. The copper discs had a good thermal capacity and enhanced heat exchange characteristics in comparison to the cotton applicators, and they also provided an opportunity to exert pressure on the lesion. Tissue destruction to a depth of 7 mm became possible, which was certainly an improvement in technique, yet the freezing of large areas of tissue as is needed in the treatment of cutaneous malignancies was not easy.

The Era of Modern Dermatologic Cryosurgery

The development of cryosurgery as a modern therapeutic technique received a major boost by the introduction of an automated cryosurgical apparatus by Cooper and Lee³⁶ in 1961. The apparatus used liquid nitrogen in a closed system that permitted continuous and rapid extraction of heat from tissue, and it featured controls that regulated the temperature of the freezing surface of its probe. It was originally designed to produce a cryogenic lesion in the brain for the treatment of Parkinsonism and other neuromuscular disorders. Cooper, a neurosurgeon, and his associates in New York stimulated considerable interest in cryosurgery by their reports of its use in diseases of the basal ganglia, brain tumors, visceral cancer, and disorders of the eyes.^37–42 After development of this apparatus it was obvious that it had wider usefulness in several specialties of medicine including dermatology. The rapid growth in the use of cryosurgery following this can be attributed to Cooper's monumental work.⁴³

Two American dermatologists, Douglas Torre, in New York, and Setrag Zacarian, in Springfield, Massachusetts, contributed substantially to the development of modern dermatologic cryosurgery by the development of an apparatus specially suited to dermatologic practice and to the needed educational programs (Figures 1 and 2).

Douglas Torre was also an inventor well versed in thermodynamics and cryogens. He used Cooper's apparatus for skin diseases, but quickly found it too bulky and expensive for office use so he modified it. Working with cryogenic engineers in 1964 and 1965 (from Linde Division, Union Carbide Corp., Danbury, CT), especially George Garamy, Torre^1,44,45 developed a nitrogen spray device that could also be used with cryoprobe tips of various sizes and shapes, converting the conduit line to a closed system. Thus, in addition to benign lesions, many types of basal and squamous cell carcinomas became amenable to cryosurgical management. In 1988 he coauthored a book with Lubritz and Kuflik on the practical aspects of cryosurgery.⁴⁶

In 1967 Setrag Zacarian described a similar device that was effective, but this unit too would prove unpopular because of its size, portability, and long conduit lines.⁴⁷ Working with the engineer Michael Bryne (Brymill Corp., Vernon, CT), in 1968, he reported on the development and use of a handheld spray device using liquid nitrogen. After some modifications this became the first commercially available handheld cryosurgical device (Figure 3).⁴⁸ Zacarian³⁰ published his research and clinical data in a monograph in 1969, and followed this with two additional books.^49,50

Interest in clinical cryosurgery and research burgeoned in several areas of medicine as well as dermatology. Andrew Gage, a surgeon, undertook laboratory research that had important implications for cutaneous cryosurgery (Figure 4). In 1965 Gage et al.⁵¹ reported on the efficacy of cryotherapy in oral cancer. Gage⁵² reported the treatment of inoperable rectal cancer with cryotherapy. He was also instrumental in organizing the Society of Cryosurgery, the American College of Cryosurgery, and for bringing dermatologists together with physicians in other specialties to share their knowledge of cryosurgery. In 1990 he coauthored a book with Kuflik that included a review of cryobiology and the cryosurgical treatment of skin cancer.⁵³

With the awareness of this new treatment modality, a number of dermatologists in the United States began to incorporate cryosurgery into their practices for a variety of lesions. In addition to Zacarian, Torre, and Gage, they included Emanuel Kuflik, Gloria Graham, Ronald Lubritz, Richard Elton, and William Spiller (Figures 5–7). They organized dermatocryosurgical seminars and workshops to disseminate their knowledge, beginning with symposia sponsored by the Rudolph Ellender Medical Foundation between 1974 and 1978, in New Orleans. They eventually became the core faculty for cryosurgery courses at the American Academy of Dermatology, begun in 1979, and for more than two decades these physicians would see much educational service together. They were joined by Drs. Gilberto Castro-Ron, Lazlo Biro, Jack Waller, Bobby Limmer, and Rachel Spiller. It should be noted that, with a few notable exceptions, a major portion of the education of American dermatologists in cryosurgery was by this small group of private physicians.

Over the years, Kuflik^54,55 has shown the value of cryosurgery for difficult and large malignant lesions, periungual warts, and for conditions that had not previously been treated with this modality. In addition, he conducted clinical research, published many articles and chapters, and is the coauthor of two books on cryosurgery.^3,46,53,56 Graham⁵⁷ pioneered the use of cryotherapy for acne, and published numerous articles and chapters. Lubritz⁵⁸ was instrumental in establishing cryotherapy as a primary form of treatment for actinic keratoses, and coauthored a book on cryosurgery with Torre and Kuflik.⁴⁶

In addition, there was also much interest in dermatologic cryosurgery in other countries. Castro-Ron, in Caracas, Venezuela, pioneered cryosurgery for the treatment of large hemangiomas, showing its value in the treatment of large skin cancer, and for palliation. He travels extensively to lecture and is largely responsible for the formation of the Ibero Latin American Society of Cryosurgery. In Great Britain, Dawber, Shepherd, Sonnex, and Holt conducted needed clinical research. Turjansky and Stolar⁵⁹ in Buenos Aires, have attained much clinical experience and published a Spanish-language book on cryosurgery. In Portugal, Goncalves showed the value of cryosurgical management for large and inoperable tumors. Breitbart, in Germany, pioneered the use of ultrasound for monitoring cryosurgery.

The new pioneering devices led to the development of several models of cryosurgical units.^60–62 Today the dominant unit in use is the handheld device containing liquid nitrogen, most commonly used as a spray, and less often with a cryoprobe, also known as contact therapy (Figure 8).⁶³ Liquid nitrogen is the most versatile cryogen, and the only one that should be used for skin cancer. While other cryogenic agents are available (nitrous oxide, CO₂, fluorinated hydrocarbons, argon, etc.), they are not recommended for cancer; rather they are used for lesions that require lesser degrees of freezing. New equipment is currently being developed to monitor the progress of freezing of skin cancer with ultrasound, already used intraoperatively for tumors of the prostate and liver.^64–66

In the 1980s, in a reappraisal of the enthusiasm for cryosurgery, some uses of freezing techniques fell from favor, some remained useful but of minor importance, and others were modified. An important change in therapy was the lowering of the freezing temperature in the management of basal and squamous cell carcinoma.⁶⁷ Although most skin diseases are treated with the sole control of clinical judgment, the measurement of tissue temperature with thermosensors is good for ascertaining that lethal temperatures are reached in the target tissue.^{4,46,55,67,68} The goal of treatment was to attain a temperature of -50°C to -60°C throughout the tumor.⁶⁹ The techniques developed by Torre, Zacarian, and Gage are essentially those in use today.

Dermatologic cryosurgery has become accepted clinical practice and the number of physicians using cryosurgical techniques has steadily increased to the point that it has reached an indispensable status in dermatologic practice. More than 50 types of benign lesions and dermatoses are considered amenable to cryosurgery, including such diverse conditions as cystic acne, chromomycosis, dermatofibroma, leishmaniasis, molluscum contagiosum, myxoid cyst, venous lake, periungual verrucae, and others (Table 1).³ Premalignant lesions such as actinic keratosis, lentigo maligna, Bowen's disease, keratoacanthoma, and actinic cheilitis are treated.^59,70,71

Results in the treatment of skin cancer with cryosurgery were found to be competitive with those provided by other therapeutic techniques. Selected difficult basal and squamous cell carcinomas, some recurrent ones, and those in the very elderly could be managed advantageously with cryosurgery. Zacarian⁷² reported his results in a large series of patients. Graham and Clark,⁷³ and Kuflik and Gage^53,74 reported high cure rates in large series of patients with basal and squamous cell carcinomas. The latter also reported on the treatment of recurrent basal cell carcinoma with cryosurgery.⁷⁵

During the past decade cryosurgery has achieved textbook status.^76–78 The task force on cryosurgery published the “Guidelines of Care for Cryosurgery.”⁷⁹ Kuflik, Gage, Graham, and Castro-Ron contributed significantly to the advancement of cryosurgery by continuing to publish their findings, and also by lecturing worldwide to report their experience.^3,80 In addition, more dermatologists became involved with teaching cryosurgery including Zouboulis, Abramovits, Chiarello, Larko, Nordin, Suhonen, Ferrar, Vozmediano, and others.

Cryosurgery has now reached a status that is unique and advantageous in its application for diverse cutaneous lesions, for the well-known indications as well as for new ones that are still being described.

In Memoriam

Douglas Torre, MD (1919–1996) and Setrag A. Zacarian, MD (1921–1998).

 

References