History of Cryosurgery
Nikolai N. Korpan The use of cold temperatures as a promising technique for medical purposes has been known for a long time. It was the anesthetizing properties of cold that were first used to treat a variety of medical condi­tions. In comparison, the history of cryosurgery is relatively short and, in the nineteenth and twentieth centuries, closely interwoven with developments in low-temperature physics, engineering and the refine­ment of the necessary instruments. A review of the history of cryosurgery will show that it has progressed in leaps and that each leap has usually been triggered by technological innovations which immediately preceded it. Thus the possibility of creating very low temperatures of less than -100°C was immediately followed by Schroeder's discovery in 1997 that the application of such low temperatures could induce cell death. The destruction of diseased tissue such as benign and malignant neoplasms by the application of ex­ceedingly low temperatures is today known by the name of cryosurgery, and is generally accepted as a valu­able optional treatment in several fields of medicine.
The damage that cold can do have been recognised from the earliest times and is referred to in both civilian and military sources. His­torical accounts of the effect of cold climates on various body tissues foreshadow the far-reaching changes that modern cryosurgical methods have brought about (Shepherd and Dawber 1982).

Ancient Egypt Already in 2500 BC, the use of cold compresses to treat compound skull fractures and infected wounds is mentioned in the Edwin Smith Sur­gical Papyrus (Breasted translation 1930).

Antiquity In 460 Be, Greek medicine was concerned with the prevention and cure of illness caused by cold. Hip­pocrates, the father of medicine, noted the effects of cold on the inhabitants of countries with cold climates. He advocated the use of cold to control hemorrhages and reduce the swelling of painful joints (Zonnevylle 1981). In 25 AD Celsus described the appearance of the skin after cold injury, and noted that if the injury was severe, dry gangrene super­vened (Shepherd and Dawber 1982). The loss of sensation which accom­panies injury from cold is described by Galen in his treatise (70 AD) "Pain as a means of diagnosis" (Shepherd and Dawber 1982). Military campaigns in the moun­tainous regions of the ancient world resulted in cold injuries of epidemic proportion. The Carthaginian mer­cenaries in Hannibal's army which crossed the Alps in 218 BC found that smearing their bodies with oil was an effective means of prevent­ing frostbite, which nevertheless took a heavy toll (Shepherd and Dawson 1982). The forces of Alex­ander the Great found similar pro­tection using sesame juice.

Eleventh Century An unknown Anglo-Saxon monk 0050 AD) employed cold as a local anesthetic (Gratton and Singer 1952).

Sixteenth Century Refrigeration anesthesia was known to Italian physicians by 1570 (Davi­son 1959).  

Seventeenth Century In 1661 Thomas Bartholin of Co­penhagen described the use of cold as a therapeutic for a variety of everyday illnesses (Bracco 1980). In 1665 Robert Boyle published a monograph on the influence of cold on living animals (Breasted 1930).

Eighteenth Century In 1714 Fahrenheit invented the mercury thermometer, which was later reinvented by Reaumur (1739) and Celsius (1742) (Walder 1966). The invention of the thermometer is of considerable importance because it was now possible to measure the actual "coldness" or temperature at which phenomena occurred. Fur­thermore, endeavors to generate lower and lower temperatures could now begin. Scientists were now able to standardize their experiments and exchange results (Schreuder 1997).

The effects a temperature of -24°C had on insects, fish, amphibians, reptiles, birds and mammals was investigated by Spallanzani in 1787. He also established the existence of water at sub-zero temperatures without it becoming ice - a physical state later called "supercooling" (Walder 1966).

During the War of Independence (1775-1783), a medical diarist, Dr. James Thatcher, noted the serious losses of American forces due to cold injuries. He recorded that on one sortie five hundred troops were "slightly frozen" after a night in the open. In the Napoleonic Wars, Napoleon's surgeon-general, Von Larrey (1766-1842), made detailed observations of the effects of cold on his patients. He described erythema and blistering of the skin after freezing, and also noted that gangrene was not an inevitable consequence of freezing if exposure was not prolonged. Uneventful healing of wounds affected by cold was also described. Tissue cooling by surface application of snow and ice was used to facilitate amputation in Napoleon's Grand Army (Schechter and Sa rot 1968).
Casualties in later campaigns were numerous, amounting to 115000 in World War I (Shepherd and Dawber 1982).

Nineteenth Century The therapeutic effects of low temperatures have been known for many years. The first successful treatment of malignant disease in England was reported between 1845 and 1851 by Dr. James Arnott (1797-:1883), who used iced saline solutions at temperatures of -18° to -24°C for the treatment of advanced breast and uterine cancer. He observed that "congelation arresting the accompanying inflammation and destroying the vitality of the cancer cell, is not only calculated to prolong life for a considerable period, but may, not improbably, in the early stage of the disease, exert a curative action" (Arnott 1850; Bird 1949). Thus Arnott is most probably the first doctor who used cold to treat malignancies. Although he did not cure them, he considerably reduced the morbidity of cancer, especially the pain, which is still sometimes a considerable problem. Most of his work focused on the application of cold in anesthesia.
The anesthetizing characteristics of low temperatures were already known by this time, but using low temperatures to destroy parts of a tumor was now recognized as an added effect of freezing. Although Arnott's contemporaries acknowl­edged the usefulness of applying cold and began to use freezing techniques locally, further devel­opments in cryosurgery had to await technological advances, especially the development of better cryogenic agents (Gage 1998).
Esmarch's approach in 1862 was courageously outspoken: "The ap­plication of cold as a means of fighting hyperemic and inflamma­tory conditions is not given the recognition it deserves by a not inconsiderable number of contem­porary physicians. Although the number of doctors who deny the antiphlogistic properties of cold is not great, many consider it dispen­sable. I therefore fully expect and am prepared to face forceful contradic­tion from many sides when I say that of all the means we have at our disposal to fight inflammatory pro­cesses, I consider cold to be the most important. Indeed, without this means, I would rather not be a surgeon." In 1868 Samuel locally froze the ear of a rabbit by means of an ether spray and described the subsequent clinical and microscopic changes that occurred (Samuel 1868).

In 1883 Open chow ski attempted to localize the physiological function of different areas within the cerebral cortex of dogs by local freezing. He obtained freezing temperatures by using the evaporation of ether in the form of a jet of warm air. Peripheral convulsions or paralyses produced by applying this method made functional mapping of the cortex possible.

The end of the nineteenth century witnessed several major discoveries in the field of cryogenics. Ether sprays described by Richardson (1866), and ethyl chloride described by Redard (1891) were used for cold analgesia but not for destructive freezing (Davison 1959).

In 1877 Cailletet in France and Pictet in Switzerland began developing adiabatic expansion systems for cooling gases. This led to the lique­faction of oxygen, air and nitrogen. Liquid air (-190°C) was first clini­cally used by Campbell-White in 1889 for the treatment of diverse skin diseases (White 1899, 1901). The liquid air was applied locally by means of a swab, spray or brass roller device.

Solidified carbon dioxide (-78.5°C) was first used by Pusey in 1907 and, subsequently became an established therapeutic technique in dermato­logy and gynecology (Pusey 1907). After 1910, apparently, liquid air was little used. The most popular cryogenic agent in the early 1900s was solid carbon dioxide.

Twentieth Century Until the beginning of the twentieth century, those who used the devices which generated cold had usually also invented them. After the turn of the century the two professions separated. Greater engineering know-how was required to improve the equipment for developing cryo­surgical instruments and for the production of cryogenic media (Schreuder 1997).

In the 1920s liquid oxygen (-182°C) began to be used clinically as a cryogenic agent in the treatment of skin diseases. Liquid oxygen is po­tentially dangerous because it burns and explodes easily, and it has therefore never become a popular cryogen for cryosurgery (Kile and Welsh 1948). In 1942 the development of chloro­fluorocarbon refrigerants led to the first closed-cycle refrigeration sys­tem in cryosurgery. Temperatures as low as -40°C could now be applied (Hall 1942). It was used for the treatment of chronic cervicitis. The device permitted rapid defrosting which released the applicator when required. These cryogens with closed refrigeration cycles never became popular. The temperatures which they can achieve are probably higher than those which can be achieved with the relatively less expensive solid carbon dioxide (Gage 1998).

Between 1936 and 1940 Temple Fay, an American neurosurgeon, used local and general refrigeration tech­niques to treat patients with advanced cancer, glioblastoma, Hodgkin's disease and other ill­nesses including large, symptomatic, inoperable cancers of the uterine cervix and the breast (Fay 1959).

In the early 1940s, Kapitsa in the Soviet Union and Collins in the United States began developing commercial techniques for the large ­scale liquefaction of hydrogen and helium, with liquid nitrogen as an abundant and low-cost by-product. Liquid nitrogen (-196°C) became commercially available, and, in 1950, this cryogen was introduced to clin­ical practice by Allington (Allington 1950). The liquid nitrogen was ap­plied with a cotton swab, and was soon commonly used to treat skin diseases and diverse non-neoplastic lesions. It was not commonly used for skin tumors because the swab technique produced only superficial' freezing, perhaps 2 mm in depth (Gage 1998). Prior to the 1960s, the devices used for cryosurgery were not efficient and were only able to freeze to a depth of several millime­ters. With a few exceptions, there­fore, freezing was primarily used for the removal of superficial layers of undesirable tissue, most often in dermatology and gynecology.

The Era of Modern Cryosurgery The development of cryosurgery as a therapeutic technique received a major stimulus from the introduc­tion of the first cryosurgical system capable of delivering liquid nitrogen (-196°C) to trocar type probes with an insulated shaft and a conductive metal tip. This was the result of the combined work of Irving Cooper, a neurosurgeon, and Arnold Lee, an engineer (Cooper and Lee 1961). Their cryosurgery probe was in essence the prototype from which all future cryosurgical probes using liquid nitrogen were built (Gage 1998). The ability of the device to produce an avascular cryolesion in the liver was demonstrated on a cat (Cooper 1963). The design of the probes allowed surgeons for the first time to treat lesions deep within parenchymal organs with minimal trauma to the remaining organ. After the introduction of the new cryosurgical probe by Cooper and Lee, cryosurgery experienced a rapid growth which lasted to the end of the decade.

In the 1960s Zacarian and Adham 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 their application to the skin (Zacarian and Adham 1966, 1967). The copper discs had a good thermal capacity and enhanced heat exchange characteristics in compari­son to the cotton applications. 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 needed to treat cutaneous malignancies was not easy (Kuflik et al. 2000).

In Kiev in the 1980s, Nikolai N. Korpan, a surgeon, began basic theoretical, experimental and clinical studies on modern cryosurgery, in co-operation with Jaroslav V.Zharkov, an engineer and designer. They developed new, highly-efficient universal cryogenic techniques with liquid nitrogen that were designed especially for the treatment of a wide variety of malignant tumors, and have since been awarded numerous patents. Drawing on their extensive know-how, the two scientists formu­lated the basic clinical and technical requirements for modern cryosur­gery, most importantly the need to freeze tissue at extremely low tem­peratures followed by deliberate thawing. The concepts underlying the design and production of the most technically advanced cryosur­gical equipment used today in dif­ferent fields of medicine were elaborated by Korpan and Zharkov (Korpan et al. 1985, 1987, 1996, 1997, 2000; Zharkov et al. 1985, 1997, 1998, 2000).

During the following twenty years, the cryosurgical treatment of tumors in various organs such as the liver (Korpan et al. 1985; Adam et al. 1997), pancreas (Korpan et al. 1985, 1997,2000), rectum (Korpan 1985, 1996; Heberer et al. 1987; Yamamoto et al. 1989; Neijer et al. 1996), breast (Korpan 1981, 2000; Rand et al. 1987; Tanaka 1995; Staren et al. 1997), skin (Dawber et al. 1992; Goncalves 1997; Nordin et al. 1997; Zouboulis 1998), lung (Katz 1989; Homasson et al. 1993; Maiwand 1999), brain (Stellar 1993), prostate (Wong et al. 1997; Chinn 1999), uterus (Andersen et al. 1988), oral cavity (Gage 1976; Pogrel et al. 1996), bone (Malawer et al. 1988; Aboulafia et al. 1994; Schreuder 1997), and cardiac surgery (Watanabe et al. 1996; Crawford and Gillette 1997) was reported.

In the 1990s the development of in-­traoperative ultrasound and its use to monitor the process of freezing renewed interest in cryosurgery (Marron et al. 1992; Onik et al. 1993; Crawford and Gillette 1997; Staren et al. 1997). The ultrasound image identified the site of the lesion, guided the placement of the cryo­probe into the lesion, and monitored the freezing process. This was a substantial advantage over the earlier techniques (Gage 1998). In addition, the development of an array of endoscopic and percutaneous access devices stimulated the use of cryo­surgery in the treatment of visceral disease, especially for tumors. Until recently, the devices used for cryosurgery were not efficient and were only able to freeze the lesions of superficial skin layers. The application of modern cryosurgery can only become possible if highly efficient cryo technology is used. Experience in the use of cryosurgery to treat uterine fibroids and malignant tu­mors of the kidney, breast, pancreas and other organs is now beginning to be gathered (Marron et al. 1992; Sta­ren et al. 1997; Uchida et al. 1995; Pitrof et al. 1994; Korpan and Hochwarter 1997).

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