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1-1 History of Cryosurgery

Kecheng Xu


  1. Cryosurgery both an old and new technique, and has gone through a long-term process of development. The history of ‘modern’ cryosurgery is relatively short and is closely intertwined with developments in low temperature physics, engineering, and instrumentation that were made during the last century
  2. The cryosurgical probes developed in the 1960's enable the precise application of cryosurgical treatment deep in the body. This unique ability let cryosurgery very promising and resulted in the expansion of the method during this era. Cryosurgery was applied to the uterus tumors, neurology, orthopedics and skin diseases
  3. From the end of the 20th century, the development of imaging technique and new freezing equipments has resulted in the formation of modern cryosurgery. Liquid nitrogen operative system and argon-helium surgical system are representatives of two important stages of modern cryosurgery
  4. Now cryosurgery has been successfully used for treatment of a variety of tumors, including benign and malignant neoplasms of prostate, lungs, liver, kidneys, breasts, uterus, ovary, bone and soft tissue
  5. From the early of the 21st century, modern cryosurgery has been applied in China and more then ten thousand patients with tumors have received cryosurgery. China has become the one of countries in which cryosurgery has been most popularly used


Cancer has become one of the major causes of mortality in our modern society and has taken the place of cardiovascular diseases to the number one killer in the world. Just in the year 2002, 28% of all deaths in Asia were linked to cancers and this mortality rate was expected to grow rapidly. Hitherto, the common treatments for cancer include surgical removal, radiotherapy and chemotherapy. These treatments could cause devastative side effects which can potentially weaken cancer patients.

A new way of thinking must, thus, prevail in the future of cancer research and treatment. New disguise and treatment methods should enhance the healing rate of the cancer disease. Modern cryosurgery experiences nowadays an international attention and dissemination.

Cryosurgery, sometimes referred to as cryotherapy or cryoablation, is an old and new technique, and has gone through a long-term process of development (Table 1-1-1). There was evidence for the use of cold in medicine as early as 3500 BC for the treatment of infected wounds. However,the history of ‘modern’ cryosurgery is relatively short and is closely intertwined with developments in low temperature physics, engineering, and instrumentation that were made during the last century[1,2].

The ancient Egyptians, and later Hippocrates, were aware of the analgesic and anti-inflammatory properties of cold, which were used to treat infection lesions of the chest, fractures of the skull, and various battle injuries. Over the past 200 years cold treatment has evolved from generalized application such as hydrotherapy (Figure 1-1-1) to specific, focal destruction of tissue—today's cryosurgery.

Figure 1-1-1. A man self-administering hydrotherapy. Wellcome Library, London

The use of freezing temperatures for the therapeutic destruction of tissue began in England in 1845-1851 when James Arnott[3] (1797-1883) , an English physician, described the use of iced-salt solutions (about-20°C) to freeze advanced cancers in accessible sites, producing reduction in tumor size and amelioration of pain and local haemorrhage[4]. His brother, a scientist, had already gained fame and fortune as inventor of the slow combustion stove. Arnott used a mixture of salt and crushed ice for palliation of tumors. Arnott was the first person to use extreme cold locally for the destruction of tissue. He stated that a very low temperature would arrest every inflammation which was near enough to the surface to be accessible to its influence[3]. He designed an equipment, consisting of a waterproof cushion applied to the skin, two long flexible tubes to convey water to and from the affected part and a reservoir for the ice/water mixture and a sump. He exhibited this at the Great Exhibition of London in 1851 and won a prize medal for his effort[4]. Arnott[3] treated breast cancer, uterine cancers and some skin cancers. Although palliation was his main aim he recognized the potential of cold for curing cancer. He advocated cold treatment for acne, neuralgia and headaches, achieving temperatures of -24°C. In addition he recognized the analgesic `benumbing’ effect of cold, recommending the use of cold to anaesthetize skin before operation. He was concerned about the safety of the new anaesthetic agents that were being introduced and advocated the use of cold as an alternative. This was to become a lifelong crusade that was ultimately unsuccessful, but his contribution to the development of cryosurgery was crucial.
In the late 1800s, along with tremendous scientific advance, there was an interest in liquefying gases. Cailletet[5], on Christmas Eve 1877, demonstrated at the French Academy of Science that oxygen and carbon monoxide could be liquefied under high pressure. Pictet[6] also demonstrated the liquefaction of oxygen but used a mechanical refrigeration cascade. Von Linde was responsible for the first commercial production of liquid air in 1895, which led the way to its widespread introduction.
Campbell White[7,8], of New York, reported his success in 1899, advocating liquid air for the treatment of a large range of conditions including lupus erythematosus, herpes zoster, chancroid, naevi, warts, varicose leg ulcers, carbuncles and epitheliomas, became the first person to employ refrigerants for medical use. He showed`the efficiency of liquid air in the treatment of carcinoma’, and enthusiastically stated that `I can truly say today that I believe that epithelioma, treated early in its existence by liquid air, will always be cured[8].
Whitehouse[9] reviewed the effects of liquid air on normal skin, finding it to be especially useful for epitheliomata, lupus erythematosus and vascular naevi. He stated that liquid air `outranks some of the remedies on which we have placed great reliance’. He treated recurrences of epitheliomata after radiotherapy and found liquid air to be more successful than repeat radiotherapy. Bowen and Towle [10] reported the successful use of liquid air for vascular lesions in 1907.
Around the time that liquid air was being investigated, William Pusey [11] of Chicago popularized the use of carbon dioxide snow (or carbonic acid snow) in preference to a salt and ice mixture. He advocated carbon dioxide snow because of its easy availability. Liquid air was very difficult to obtain at this time. The liquid carbon dioxide gas was supplied in steel cylinders under pressure. When the gas was allowed to escape, rapid expansion caused a fall in temperature (the Joule—Thompson effect) and a fine snow was formed. The snow was easily compressed into various shapes, known as pencils, suitable for different treatments. Pusey’s first reported case [11] was the treatment of a large black hairy naevus on a young girl’s face. Impressive before-and-after photographs showed the successful depigmentation of the lesion. This was one of the first demonstrations of the extraordinary sensitivity of melanocytes to cold. He successfully treated other naevi, warts and lupus erythematosus. Pusey stated of carbon dioxide snow that `we have found a destructive application whose action can be accurately gauged and is therefore controllable’. He recognized the low scarring potential of cryosurgery although he attributed this to regeneration of residual epidermal cells rather than to collagen’s resistance to cold.
Hall-Edwards[12], of Birmingham, first described his carbon dioxide collection modelin The Lancet in 1911. Hall-Edward’s monograph, written later in 1913, detailed the uses of carbon dioxide and methods of collection (Figure 2). His contribution to cryosurgery was all the more remarkable, and would have been well aware of the place of cryosurgery in relation to X-ray use. He detailed many conditions in which treatment was effective but was particularly struck by its efficacy in rodent ulcers. At the same time Cranston-Low[13], a physician in the Edinburgh skin department, was likewise promoting the use of carbon dioxide snow. He observed that `thrombosis, direct injury to tissues, and the inflammatory exudates probably all act together’ to produce the effects of freezing.

Figure 1-1-2. Hall-Edward’s carbon dioxide snow collector and compressor

Solid carbon dioxide applied directly to the skin cannot get the surface temperature below -79°C. This was insufficient for deeper freezing of tissue necessary for treatment of malignancies, when a temperature of -50°C at a tissue depth of 3 mm was required. Nevertheless it was proved very successful for a wide variety of benign skin conditions and remained popular until the 1960s. De Quervain reported the successful use of carbonic snow for bladder papillomas and bladder cancers in 1917[14].
Some ingenious devices were developed including Campbell White’s roller for treatment of erysipelas[15]. Grimmett[16]highlighted the limitations of a cotton wool applicator, showing that the depth of freeze was insufficient to treat tumours. Whitehouse (1864-1938), a New York dermatologist, developed a spray in 1907 which allowed much lower minimum temperatures. His simple design consisted of two glass tubes inserted into a cork stopper of a laboratory wash bottle, operated by finger control. Whitehouse used his spray to treat skin lesions including cancers but abandoned it because of the difficulty in limiting the area of the spray. The great advantage of liquid air over salt/ice mixtures was the lower temperatures that could be achieved, allowing tumors to be treated, but a disadvantage was the difficulty in obtaining and transporting it. Sir James Dewar solved the problems of transportation and storage by inventing a flask made of two walls of glass with a vacuum between. Even today the containers used for refrigerants have much the same design.
Allington[17] was the first who used liquid nitrogen, in 1950. He recognized that the properties of liquid nitrogen were very similar to those of liquid air and oxygen. He used a cotton swab for treating various benign lesions. But poor heat transfer between swab and skin meant this method was insufficient for tumour treatment.
With the development of modern cryosurgical apparatus by Cooper[18] in 1961, a resurgence of interest in cryosurgery was initiated and techniques for diverse clinical conditions, including visceral cancer.
Irving S. Cooper (1922-1985) worked his way through high school, college, and medical school to become one of the pioneers in functional neurosurgery. In 1913 he designed a liquid nitrogen probe that was capable of achieving temperatures of -196°C. With it he treated Parkinson’s disease and other movement disorders by freezing the thalamus, in addition to previously inoperable brain tumors. Cooper’s work led to an explosion of interest in liquid nitrogen and its eventual acceptance as a standard treatment in manyspecialties. After the initial widespread clinical trials matured in the 1970s, some applications of the technique fell into disuse while others became standard treatment[19].
More general use of cryosurgery was facilitated by the development of devices suitable for office based practice. Zacarian[20] developed a hand-held device. His spray allowed one-handed operation with trigger type control, and interchangeable tips permitted variations in spray diameter[21]. Zacarian also developed copper probes that allowed tissue-freezing to depths of up to 7 mm. His contributions to cryosurgery equipment, understanding of the science of the cryolesion and the published work on cryosurgery were very great.
Amoils[22] developed a liquid nitrogen probe that achieved cooling by expansion. He performed cataract extraction (cryoextraction) successfully while cooling was slow and temperatures were not low enough for tumour work. This system is still widely used in gynaecology and ophthalmology. The use of liquid nitrogen spread through different specialties[21]. Rand performed a transphenoidal hypophysectomy with liquid nitrogen, Gage treated oral cancers and Cahan performed cryosurgery of the uterus with a liquid nitrogen probe. The use of liquid nitrogen in Great Britain took off when Zacarian donated the first hand-held liquid nitrogen spray to the Oxford dermatology department in the 1970s. This centre became the focus of cryosurgical research in Britain.
Table 1-1-1. History of cryosurgery






Old Greece


Treatment of infected wound

11th century







Treatment of gout


Faraday M

Ice and salt water

Freezing tumor


James Arnott

mixture of salt and crushed ice

freeze advanced cancers



Liquided oxygen and nitrogen

Making low-temperature



Development of the first vacuum flask for facilitated storage and handling of liquefied gases


Campbell White

First to use refrigerants for medical practice


Linde,Germany ;Hampson,UK

Use of the Joule-Thomson effect to produce continuously operating air liquefiers



Use liquid air for epitheliomata


Pussey William

Solid CO2

Establishment of cryotherapy



Described carbon dioxide collection model



Kapitsa; Collins

Liquid hydrogen and nitrogen

Making liquid nitrogen



Low temperature

Treatment of tumor



Liquid nitrogen

Use of treatment in dermatology and gynecology



Mixture of ethanol



Cooper, USA

Liquid nitrogen

Treatment of diseases of central nervous system



Liquid nitrogen probe




Liquid nitrogen

Treatment of prostate cancer and liver cancer



N2O cryo-apparant

Treatment of benign prostate proliferation



Develop copper probe

Treatment of deep lesions

90’s 20th century


Liquid nitrogen

Treatment of tumors of prostate,liver and kidneys



Argon-based cryosurgical system

Treatment of prostate cancer and liver cancer approved by FDA,USA



Argon-based cryosurgical system

Clinical use approved by CE,1999, and by FDA, USA,2000

After 2000

USA, China

Argon-based cryosurgical system

Treatment of tumors of liver, lungs, kidneys and pancreas



From end of 20th century, cryosurgery has a great development. This results from a more in-depth survey of three important topics in cryosurgery: (a) the biochemical and biophysical mechanisms of tissue destruction during cryosurgery, (b) New freezing equipments, and (c) monitoring and imaging techniques for cryosurgery.

Of freezing equipments, liquid nitrogen operative system and argon-helium operative system are representatives of two important stages of modern cryosurgery. The greatest advance in the technology is the use of argon gas to drive ice formation using a principle known as the Joule-Thomson effect. The thin, highly efficient probes, available in several sizes, can be placed in diseased sites via endoscopy or percutaneously in minimally invasive procedures. This gives physicians excellent control of the ice, and minimizing complications using ultra-thin 17 gauge cryoneedles [23-25].

Another technological advances which has caused renewed interest in cryosurgery is the development of intraoperative ultrasound to monitor the therapeutic process. The manner of use is to place the probe in the desired location in the diseased tissue with ultrasound, CT or MRI guidance. If required by the size or location of the tumor, multiple probes can be inserted and cooled to -160oC simultaneously.

Clinical applications have become common in the past 10 years. The cases selected for cryosurgery are generally those for which no conventional treatment is possible. However, especially in prostatic cancer, the operative morbidity is so low and the results of therapy are sufficiently good in the short term to merit consideration of use in earlier stages of the disease. Diseases which are adaptable to cryosurgery include not only prostatic cancer and liver tumors, but also diverse tumors in other sites, such as the lung, brain, breast, bone, pancreas, kidney, and uterus[26].

During this period, large amount of experimental and clinical research have emerged. 14 International conferences of cryosurgery have been held in Europe and Asia. Current president of International Society of Cryosurgery, Dr Franco of Italy contributes signifinantly to the development of cryosurgery over the world. Magazines <Cryobiology> have been published for 57 volumes. About 29 000 papers with relevant information on cryosurgery for cancer are published in a variety of academic magazines according to an online PubMed search using keywords “cryosurgery”, ”cryoablation” and “cryotherapy”.
In the past years, many scholars have made leading work, for example:

  • Prostate cancer cryosurgery: Onik GM[27] (USA), Bahn DK[28] (USA), Cohen JK[29] (USA)
  • Open cryosurgery of liver cancer: Zhou XD[30] (China), Seifert JK[31] (Germany), Mala T [32] (Norway), Adam R[33] (France)
  • Laparoscopic cryosurgery of liver cancer: Lezoche E[34] (Italy)
  • Percutaneous cryosurgery of liver cancer: Nakazaki H [35] (Japan), Xu KC and Niu LZ [36] (China)
  • Endobronchial cryosurgery of lung cancer: Maiwand MO[37] (UK)
  • Open cryosurgery of lung cancer: Maiwand MO[37] (UK)
  • Percutaneous cryosurgery of lung cancer: Kawamura M[38] (Japan), Niu LZ and Xu KC[39] (China), Wang HW[40] (China)
  • Cryosurgery of pancreatic cancer: Korpan NN (Austria) [26], Xu KC and Niu LZ[41] (China)
  • Cryosurgery of breast cancer: Sabel MS[42] (USA), Kaufman CS[43] (USA), Staren ED[44] (USA)
  • Open cryosurgery of renal cancer: Delworth MG[45] (USA), Rukstalis DB[46] (USA)
  • Laparoscopic cryosurgery of renal cancer: Gill IS[47] (USA), Moon TD (USA) [48]
  • Percutaneous cryosurgery of renal cancer: Harada J[49] (Japan), Sewell PE[50] (USA), Shingleton WB[51] (USA), Gore JL[52] (USA), Kodama Y [53] (Japan)
  • Cryosurgery of uterine fibroids: Cowen BD[54] (USA), Dori M[55] (Japan), Zupi E [56] (Italy), Zreik TG[57] (USA), Duleba AJ[58] (USA)
  • Cryosurgery and immunology: Joosten JJ[59] (Netherlands), Matsumura RB[60] (Japan), Miya K[61] (Japan)
  • Cryosurgery and chemotherapy: Ikekawa S[62] (Japan), Mir LM[63] (France),Baust JG[64](USA)

Dr. Nikolai N. Korpan[26] in Austria and his colleagues together make a great contribution. In the last 22 years, he and his colleagues together in co-operation with other international scientific institutions have developed and refined new cryosurgical techniques for operative procedures in patients with liver and pancreas tumors, breast cancer, lymph node metastases, and recurrent skin cancer. Monograph <Basics of Cryosurgery > edited by Nikolai Korpan in 2001 has comprehensively described the principle and clinical application of cryosurgery in a variety of tumors (Figure 1-1-3). Just in the monograph, Dr Korpan first showed “All patients with pancreatic cancer have responded well to cryosurgery”, and “There were no surgical complications or mortality directly associated with the cryosurgery”.

Figure 1-1-3. Monograph <Basics of Cryosurgery> edited by Korpan NN, Springer-Verlag, 2007

Cryosurgery has been used in medical practice both as a single technique as well as a supplementary to other oncological treatments, and which has become an important weapon in the war with cancer.


In 1990’s, Zhou used open cryosurgery (liquid nitrogen) for treatment of 235 patients with hepatocellular carcinoma with results comparable to that of operative resection[30].This is the largest series of report of cryosurgery for treatment of solid cancer.

From the early period of the 21st century, cryosurgery using the Cryocare System (Endocare, Inc., Irvine, CA, USA) has been applied in China. More than hundred of hospitals or medical centers install the equipment. More than ten thousands patients with malignant and benign tumors have received cryosurgery. It is specially noticed that most cases of cryosurgery which were performed in China used the percutaneous approach. China has become the one of countries that cryosurgery has been most popularly used.

In 2007, the 14th International Conference of Cryosurgery was held in Beijing, China. In the same year, < Cryosurgery for Cancer> (in Chinese), which was edited by Dr. Kecheng Xu and Lizhi Niu was published in Shanghai (Figure 1-1-4). This is the first monograph in the cryosurgery field in China[65].

Figure 1-1-4. Monograph <Cryosurgery for Cancer > by edited Xu KC and
Niu LZ. Shanghai Sci-Tech-Edu Pub,China, 2007

In Fuda Cancer Hospital Guangzhou (FCHG), China, as many as more than 4500 cases of tumors underwent cryosurgery from March 2001 to December 2008. There were more than 30 kinds of malignant tumor received cryosurgery, most of which were performed through percutaneous approach. Most of the cases had better palliation effect and had curing outcome[66-72]. It should be especially pointed out that the percutaneous cryosurgery for locally advanced pancreatic cancer and centrally- located lung cancer have been performed in Fuda Cancer Hospital Guangzhou. Dr Xu Kecheng got a gold medal from the 35th Annual Meeting of the Japan Society for Low Temperature Medicine held Tokyo on November 21-23, 2008 for his achievement of cryosurgery for treatment of pancreatic cancer.

Cryosurgery is a surgical technique that employs freezing to destroy undesirable tissue. Developed first in the middle of the nineteenth century it has been recently corporated with new imaging technologies and is a fast growing minimally invasive surgical technique. It is anticipated that cryosurgery, especially percutaneous cryosurgery, will become a practical and effective modality for treatment of a variety of early and advanced cancer.


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