JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 94 April 2001

The history of cryosurgery

S M Cooper MRCP MRCGP R P R Dawber FRCP

J R Soc Med 2001;94:196±201

The controlled destruction of tissue by freezing is today

widely practised in medicine. Terms for it include
cryotherapy, cryocautery, cryocongelation and cryogenic
surgery, but cryosurgery (literally, cold handiwork) seems
most appropriate. Cryosurgery is a cheap, easy, and safe
treatment suitable for both hospital and of®ce based
practice. Its major advantage is excellent cosmetic results
with minimal scarring.
The bene®ts of cold have been appreciated for many
thousands of years. The ancient Egyptians, and later
Hippocrates, were aware of the analgesic and anti-
in¯ammatory properties of cold. Over the past 200 years
cold treatment has evolved from generalized application
such as hydrotherapy (Figure 1) to speci®c, focal
destruction of tissueÐtoday's cryosurgery.

THE BEGINNINGS OF CRYOSURGERY

James Arnott (1797±1883), an English physician, published
on the use of cold between 1819 and 18791,2. He was the
senior physician of Brighton In®rmary but moved to London
on winning fame. His brother, a scientist, had already
gained fame and fortune as inventor of the slow combustion
stove. Arnott was the ®rst person to use extreme cold
locally for the destruction of tissue. He used a mixture of
salt and crushed ice (`two parts ®nely pounded ice and one
part of chloride of sodium'1) for palliation of tumours, with
resultant reduction of pain and local haemorrhage. He
stated that a very low temperature will arrest every
in¯ammation which is near enough to the surface to be
accessible to its in¯uence1. He designed his own equipment,
consisting of a waterproof cushion applied to the skin, two
Figure 1 A man self-administering hydrotherapy. Wellcome
long ¯exible tubes to convey water to and from the affected Library, London
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 effort2. (The Great Exhibition
was a showcase for the Empire's scienti®c prowess not that the cases he had seen `are therefore, by no means
unlike the Millennium Dome but with considerably more unfavourable to the supposition of the curability of cancer
style.) Arnott treated breast cancer, uterine cancers and by congelation'. He advocated cold treatment for acne,
some skin cancers. Although palliation was his main aim he neuralgia and headaches, achieving temperatures of
recognized the potential of cold for curing cancer, stating 724 8C. In addition he recognized the analgesic `benumb-
ing' effect of cold, recommending the use of cold to
anaesthetize skin before operation. He was concerned about
Department of Dermatology, Oxford Radcliffe Hospitals, Oxford OX3 7LJ, UK
the safety of the new anaesthetic agents that were being
Correspondence to: Dr S M Cooper, Department of Dermatology, Churchill
introduced and advocated the use of cold as an alternative.
196
Hospital, Headington, Oxford OX3 7LJ, UK
E-mail: NeilCCooper@msn.com This was to become a lifelong crusade that was ultimately
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 94 April 2001

unsuccessful, but his contribution to the development of temperature (the Joule±Thompson effect) and a ®ne snow
cryosurgery was crucial. was formed. The snow was easily compressed into various
shapes, known as pencils, suitable for different treatments.
FIRST USE OF REFRIGERANTS Pusey's ®rst reported case9 was the treatment of a large
Salt/ice mixtures were not capable of reducing tissue black hairy naevus on a young girl's face. Impressive before-
temperatures suf®ciently to treat tumours effectively. It was and-after photographs showed the successful depigmenta-
not until refrigerants came into use that lower tissue tion of the lesion. This was one of the ®rst demonstrations
temperatures could be achieved. In the late 1800s, at a time of the extraordinary sensitivity of melanocytes to cold. He
of tremendous scienti®c advance, there was an interest in successfully treated other naevi, warts and lupus erythe-
liquefying gases. Cailletet, on Christmas Eve 1877, matosus. Pusey stated of carbon dioxide snow that `we have
demonstrated at the French Academy of Science that found a destructive application whose action can be
oxygen and carbon monoxide could be lique®ed under high accurately gauged and is therefore controllable'. He
pressure3. Pictet also demonstrated the liquefaction of recognized the low scarring potential of cryosurgery
oxygen but used a mechanical refrigeration cascade4. Von although he attributed this to regeneration of residual
Linde was responsible for the ®rst commercial production epidermal cells rather than to collagen's resistance to cold.
of liquid air in 1895, which led the way to its widespread Hall-Edwards, of Birmingham, ®rst described his carbon
introduction. dioxide collection model in The Lancet in 191110. Hall-
Edward's monograph, written later in 1913, detailed the
LIQUID AIR AND LIQUID OXYGEN
uses of carbon dioxide and methods of collection11 (Figure
2). His contribution to cryosurgery was all the more
Campbell White, of New York, was the ®rst person to remarkable because he was a respected radiotherapist in
employ refrigerants for medical use. He reported his charge of much of the Midlands. He would have been well
success in 1899, advocating liquid air for the treatment of a aware of the place of cryosurgery in relation to X-ray use.
large range of conditions including lupus erythematosus, He detailed many conditions in which treatment was
herpes zoster, chancroid, naevi, warts, varicose leg ulcers, effective but was particularly struck by its ef®cacy in rodent
carbuncles and epitheliomas5,6. He recognized `the ulcers. At the same time Cranston-Low, a physician in the
ef®ciency of liquid air in the treatment of carcinoma' and Edinburgh skin department, was likewise promoting the use
enthusiastically stated `I can truly say today that I believe of carbon dioxide snow12. He observed that `thrombosis,
that epithelioma, treated early in its existence by liquid air,
will always be cured6'.
Whitehouse7 reviewed the effects of liquid air on
normal skin, ®nding 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 reliance7'. He treated
recurrences of epitheliomata after radiotherapy and found
liquid air to be more successful than repeat radiotherapy.
Bowen and Towle8 reported the successful use of liquid air
for vascular lesions in 1907. Liquid oxygen had a limited
vogue in the 1920s and 1930s. It has similar properties to
liquid air, achieving temperatures of 7182.9 8C, but was
chie¯y used for acne.

CARBONIC ACID SNOW

Around the time that liquid air was being investigated,
William Pusey9 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 (thanks to its use by
manufacturers of mineral waters). Liquid air was very
dif®cult to obtain at this time. The liquid carbon dioxide gas
was supplied in steel cylinders under pressure. When the
197
Figure 2 Hall-Edward's carbon dioxide snow collector and
gas was allowed to escape, rapid expansion caused a fall in compressor
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 94 April 2001

direct injury to tissues, and the in¯ammatory exudate cancers but abandoned it because of the dif®culty in limiting
probably all act together' to produce the effects of freezing. the area of the spray. The great advantage of liquid air over
Solid carbon dioxide applied directly to the skin cannot salt/ice mixtures was the lower temperatures that could be
get the surface temperature below 779 8C. This is achieved, allowing tumours to be treated, but a
insuf®cient for deeper freezing of tissue necessary for disadvantage was the dif®culty in obtaining and transporting
treatment of malignancies, when a temperature of 750 8C it. Sir James Dewar solved the problems of transportation
at a tissue depth of 3 mm is required. Nevertheless it and storage by inventing a ¯ask made of two walls of glass
proved very successful for a wide variety of benign skin with a vacuum between11. Even today the containers used
conditions and remained popular until the 1960s. Carbon for refrigerants have much the same design.
dioxide slush, a mixture of carbon dioxide and acetone, was
used extensively for acne. As the use of carbon dioxide
snow became more widespread so did the range of LIQUID NITROGEN
conditions treated. De Quervain reported the successful Allington is generally thought to have been ®rst to use
use of carbonic snow for bladder papillomas and bladder liquid nitrogen, in 195017. He recognized that the
cancers in 191713. properties of liquid nitrogen were very similar to those of
liquid air and oxygen. After the Second World War, liquid
DEBATE ON THE BEST REFRIGERANT nitrogen became freely available and was preferable to
liquid oxygen with its explosive potential. He used a cotton
The debate on the best cryogen to use persisted for much of
swab for treating various benign lesions but poor heat
the ®rst half of the twentieth century. Reviewing the uses of
transfer between swab and skin meant this method was
liquid air and carbon dioxide snow in 1910, Gold14
insuf®cient for tumour treatment.
concluded `there is no hesitancy in saying liquid air is far
The contribution of Dr Irving S Cooper to cryosurgery
preferable' although he acknowledged the dif®culty in
was immense18,19. An American neurosurgeon based in
obtaining liquid air at that time. In 1929 Irvine and
New York, in 1913 he designed a liquid nitrogen probe that
Turnacliffe15 similarly favoured liquid air and oxygen over
was capable of achieving temperatures of 7196 8C. With it
carbon dioxide snow, but the controversy continued into
he treated Parkinson's disease and other movement
the 1960s. Irvine and Turnacliffe15 reported liquid air
disorders by freezing the thalamus, in addition to previously
treatment of seborrhoeic keratoses, senile keratoses, lichen
inoperable brain tumours. Although Cooper was contro-
simplex, poison ivy dermatitis and herpes zoster. They
versial in his lifetime because of his showmanship, his work
found liquid oxygen very useful for warts, declaring that `it
led to an explosion of interest in liquid nitrogen and its
offers a practically sure, quick and painless method for
eventual acceptance as a standard treatment in many
removal of all types of warts, including the plantar type'.
specialties. More general use of cryosurgery was facilitated
The debate was at times acrimonious. Pusey, an ardent
by the development of devices suitable for of®ce based
advocate of carbon dioxide snow, said in reply to Irvine's
practice. Torre20 developed a liquid nitrogen spray in 1965
paper, `I do not want to throw any question on Dr Irvine's
and Zacarian a hand-held device, the Kryospray, in 196720.
results with liquid air but for any method of treatment to
Zacarian popularized the use of this equipment21. Zacarian's
convince me of its adequacy in warts, I want about 10,000
spray allowed one-handed operation with trigger type
cases'15.
control, and interchangeable tips permitted variations in
spray diameter. Zacarian also developed copper probes that
APPLICATION AND STORAGE allowed tissue-freezing to depths of up to 7 mm. His
Refrigerants were generally applied either by painting contributions to cryosurgery equipment, understanding of
directly onto the skin or by use of cotton wool twisted the science of the cryolesion and the published work on
around a piece of cane that had been dipped into liquid air. cryosurgery was very great. Amoils22 developed a liquid
Some ingenious devices were developed including Campbell nitrogen probe that achieved cooling by expansion. He
White's roller for treatment of erysipelas6. Grimmett16 performed cataract extraction (cryoextraction) successfully
highlighted the limitations of a cotton wool applicator, but cooling was slow and temperatures were not low
showing that the depth of freeze was insuf®cient to treat enough for tumour work. This system is still widely used in
tumours. Whitehouse (1864±1938), a New York derma- gynaecology and ophthalmology. The use of liquid nitrogen
tologist, developed a spray in 1907 which allowed much spread through different specialties21. Rand performed a
lower minimum temperatures7. His simple design consisted transphenoidal hypophysectomy with liquid nitrogen, Gage
of two glass tubes inserted into a cork stopper of a treated oral cancers and Cahan performed cryosurgery of
laboratory wash bottle, operated by ®nger control. the uterus with a liquid nitrogen probe. The use of liquid
198 Whitehouse used his spray to treat skin lesions including nitrogen in Great Britain took off when Zacarian donated
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 94 April 2001

the ®rst hand-held liquid nitrogen spray to the Oxford acne pits and is especially useful when a large surface area
dermatology department in the 1970s. This centre became needs to be treated. The major advantages of freons are
the focus of cryosurgical research in Britain. their portability and easy storage but their disadvantages are
insuf®ciently low temperatures for tumour work, potential
CRYOBIOLOGY toxicity in inhaled air and their role in depleting the ozone
layer. Currently a spray-on non-¯uorinated hydrocarbon
The past 50 years have seen great advances in knowledge of
can be prescribed (the Histofreezer, Thames Laboratories
the biological effects of freezing. Almost all research has
UK) but this is unlikely to achieve temperatures low enough
concerned the effects of liquid nitrogen. The development
to be highly effective.
of temperature probes that can be inserted into skin has
allowed measurement of tissue temperatures during
freezing. An accurate picture of the shape and depth of DERMATOLOGICAL CRYOSURGERY
iceball formation with different lengths of freeze has been Cryosurgery is now indispensable in a dermatology
built up, allowing development of guidelines for freezing department. Benign lesions amenable to treatment include
times (best established for cutaneous lesions23). For viral warts, seborrhoeic keratoses, molluscum contagiosum,
malignant lesions freezing times are longer than for benign spider angiomata and digital myxoid cysts23. The ef®cacy of
lesions since destruction of all malignant cells is vital. Tissue treatment of viral warts is approximately 75% if lesions are
temperatures must be below 750 8C for adequate treated every two to three weeks, in line with other
treatment of tumours. A 30-second spot freeze, counted methods of treatment28. However, when cryosurgery is
30 seconds after an iceball formation, is capable of achieving contemplated for benign lesions it is especially important to
a tissue temperature of 7508C in the centre of the ice ball consider the possible side-effects of pain, blistering and
and is usually the minimum time necessary for tumour hypopigmentation.
work3. Other research has concentrated on determining the Cryosurgery is highly effective for premalignant solar
sensitivity of individual cell types to freezing. Melanocytes keratoses and Bowen's disease. Cure rates after cryosurgery
are most sensitive, hence the depigmentation of skin often of Bowen's disease are comparable with those of excision,
seen after cutaneous cryosurgery. Collagen is the most curettage and cautery29. Basal cell carcinomas are
resilient tissue, and indeed preservation of the normal commonly treated by cryosurgery and the cure rates also
structure of collagen bundles is observed on electron compare very favourably with those of surgical treatments,
microscopy even after the deep freezes necessary for in carefully selected patients. Other tumours that can be
tumour work. This explains why there is so little scarring24. effectively treated are squamous cell carcinomas and lentigo
Cartilage necrosis is extremely rare, so cryosurgery is maligna23.
particularly suitable in areas where maintenance of elasticity
and function are importantÐsuch as the ear, around the THE WIDER APPLICATION OF CRYOSURGERY
eyes and the nose25.
Many other specialties have embraced and re®ned the
technique of cryosurgery. Eye surgeons have used it
WHICH REFRIGERANT? extensively. The ®rst report of retinal tears treated by
Liquid nitrogen is by far the most popular cryogen in freezing came from Bietti30 in 1933, and when Bellowes
current use. Its popularity is due to the low temperatures reviewed cryotherapy of ocular diseases in 1966 he included
achievable (7197 8C), which make it suitable for both cryoextraction of cataracts and treatments for glaucoma and
benign and malignant lesions. Its effects are predictable and tumours30. Cryosurgery still has an important place in
well documented. Carbon dioxide still enjoys some modern ophthalmological practice, particularly for eyelash
popularity because of its easy storage but is really only ablation in trichiasis31, treatment of retinopathy of
suitable for the occasional user and for treatment of benign prematurity32 and retinal detachment.
lesions. Nitrous oxide is favoured by many gynaecologists In gynaecology the use of cold treatment goes back as far
and oral surgeons. Storage presents no problems but the as 1883, when Openchowski13 treated chronic cervicitis
large cylinders required are not easily portable. Only a with cold water irrigation. Temple Fay33, in Philadelphia,
probe method is suitable because spraying results in applied both local and general cold treatment for cervical
formation of solid crystals of nitrous oxide. A lowest tumours during the 1940s and in 1964 Cahan34 developed
temperature of 789 8C makes nitrous oxide unsuitable for the liquid nitrogen probe for the treatment of uterine
malignant lesions. Freons (¯uorinated hydrocarbons with a ®broids and cervical neoplasia. There has been some
low boiling point) have been used in dermatological practice interest in cryosurgical treatment of cervical intraepithelial
since 1955 when Wilson advocated their use for ®rming neoplasia but this is losing favour. Cryosurgery of vulval
skin before dermabrasion27. Freon 12 has been used for intraepithelial neoplasia is followed by early recurrence and 199
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 94 April 2001

is not to be recommended35. Palliation of surgically 8 Bowen JT, Towle HP. Liquid air in dermatology. Med Surg J 1907;
157:561
unresectable vulval squamous cell tumours can be very
9 Pusey W. The use of carbon dioxide snow in the treatment of naevi
bene®cial, with reduction of pain and tumour size36. and other lesions of the skin. JAMA 1935;49:1354±6
General surgeons have used freezing as an adjunct to 10 Edwards JH. The therapeutic effects of carbon dioxide snow: methods
surgery. Allen37, in 1938, recognized that limbs packed in of collecting and application. Lancet 1911;ii:87±90
ice for 3 hours could be subsequently amputated without an 11 Hall-Edwards J. Carbon Dioxide Snow: its Therapeutic Uses. London:
anaesthetic agent, and as recently as 1985 a review article37 Simpkin, Marshall, Hamilton, Kent, 1913
described the use of freezing to delay an otherwise urgent 12 Cranston-Low R. Carbonic Acid Snow as a Therapeutic Agent in the
Treatment of Disease of the Skin. Edinburgh/London: William Green,
amputation and allow more time for stabilization of a 1911
critically ill patient. A recent study of palliative treatment 13 Bracco D. The historic development of cryosurgery. Clin Dermatol
for primary rectal carcinoma showed complete relief of 190;8:1±4
symptoms in 62%38. Patients selected were unable to 14 Gold J. Liquid air and carbonic acid snow: therapeutic results obtained
undergo surgical treatment either because of prohibitive by dermatologists. NY Med J 1910;92:1276±7
operative risk or because of unresectable tumour. 15 Irvine H, Turnacliffe D. Liquid oxygen in dermatology. Arch Dermatol
Syphilol 1929;19:270±80
Cryosurgery has been shown to be an effective treatment
16 Grimmett R. Liquid nitrogen therapy. Histologic observations. Arch
for haemorrhoids39 and may be a useful alternative to Dermatol 1961;83:563±7
surgical haemorrhoidectomy in countries where health 17 Allington H. Liquid nitrogen in the treatment of skin diseases. Calif
resources are limited. Unresectable tracheobronchial Med 1950;72:153±5
carcinomas have been managed by cryosurgery40, with 18 Cooper IS. Cryogenic surgery. A new method of destruction or
haemoptysis alleviated in over 90%. extirpation of benign or malignant tissues. N Engl J Med 1963;
263:741±9
Other areas of current interest include a nephron-
19 Das K, Benzil DL, Rovit RL. Irving S Cooper (1922±1985): a pioneer
sparing treatment option for kidney cancers41 and in functional neurosurgery. J Neurosurg 1998;89:865±73
cryosurgical treatment of prostatic cancer42. In prostate 20 Zacarian S. Cryogenics: the cryolesion and the pathogenesis of
cancer, impotence and incontinence are less frequent with cryonecrosis. In: Zacarian SA, ed. Cryosurgery for Skin Cancer and
cryosurgery than with radical prostatectomy or radio- Cutaneous Disorders. St Louis: Mosby, 1985; 1±30
therapy. Further studies will be necessary to assess long- 21 Ku¯ik EG, Gage AA. History. In: Ku¯ik EG, Gage AA, eds Cryosurgical
Treatment for Skin Cancer. New York: Igaku-Shoin 1990: 1±13
term cure rates. Hepatic cryosurgery for either metastatic
22 Amoils SP. The Joule Thomson cryoprobe. Arch Ophthalmol
carcinoma or primary hepatocellular carcinoma, via cryo- 1967;78:201±7
probe, gives results similar to those of surgical resection. 23 Dawber R, Colver G, Jackson A. Cutaneous Cryosurgery: Principles and
The major advantage is the ability to treat widespread Practice. London: Martin Dunitz, 1997
lesions, whereas surgical resection is limited to isolated or 24 Shepherd JP, Dawber RPR. Wound healing and scarring after
small foci of tumour43. Also, cryosurgery has been used for cryosurgery. Cryobiology 1984;21:157±69
bone tumours for 30 years and still has a role44. 25 Dawber RPR. Cold kills! Clin Exp Dermatol 1988;13:137±50
After nearly two centuries, the technique of cryotherapy 26 Dawber RPR, Colver G, Jackson A. Historic and scienti®c basis of
cryosurgery. In: Cutaneous Cryosurgery. Principles and Practice. London:
remains widely applicable. At a time when surgical excision Martin Dunitz, 1997: 15±26
is in the ascendant this simple method, with its cosmetic and 27 Wilson JW, Ayers SW, Luikart R. Dichlorotetra¯uorethane for
functional bene®ts, should not be neglected. surgical planning. Arch Dermatol 1955;71:253
28 Bunney MH, Nolan MW, Williams DA. An assessment of methods of
treating viral warts by comparative treatment trials based on a standard
design. Br J Dermatol 1976;94:667±9
REFERENCES 29 Ball S, Dawber RPR. Treatment of Bowen's disease with particular
emphasis on the problem of lower leg lesions. Austr J Dermatol 1998;
1 Arnott J. On the Treatment of Cancer by the Regulated Application of an 39:63±8
Anaesthetic Temperature. London: Churchill, 1851 30 Bellowes JG. Cryotherapy of Ocular Diseases. Philadelphia: Lippincott,
2 Bird H. James Arnott, MD (Aberdeen), 1797±1883, a pioneer in 1966
refrigeration. Anaesthesia 1949;4:10±17 31 Bartley GB, Bullock JD, Olsen TG, et al. An experimental study to
3 Cailletet L. Recherches sur la liqueÂfaction des gaz. Ann Chemie Physique compare methods of eyelash ablation. Ophthalmology 1987;94:1286±9
1878;15:132±44 32 Anderson CC, Phelps DL. Peripheral retinal ablation for threshold
4 Pictet R. MeÂmoire sur la liqueÂfaction de l'oxygeÁne. Am Chemie Physique retinopathy of prematurity in preterm infants. Cochrane Database Syst
1878;13:145±227 Rev 2000;2:CD001693
5 White AC. Liquid air: its application in medicine and surgery. Med Rec 33 Gage AA. History of cryosurgery. Semin Surg Oncol 1998;14:99±109
1899;56:109±12 34 Cahan WG. Cryosurgery of the uterus: description of technique and
6 White AC. Possibilities of liquid air to the physician. JAMA potential application. Am J Obstet Gynecol 1964;88:410±14
1901;36:426±9 35 Marren P, Dawber RPR, Wojnarowska F. Failure of cryosurgery to
7 Whitehouse H. Liquid air in dermatology: its indications and eradicate vulval intraepithelial neoplasia: a pilot study. J Eur Acad
200 limitations. JAMA 1907;49:371±7 Dermatol Venerol 1993;2:247±51
 JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 94 April 2001

36 Almeido Gongalves JC. CryovulvectomyÐa new surgical technique 41 Gill IS, Novick AC. Renal cryosurgery. Urology 1999;54:215±9
for advanced cancer. Skin Cancer 1986;1:17±32
42 Badalament RA, Bahn DK, Kim H. Patient-reported complications
37 Hunsaker R, Schwartz J, Keasy B, et al. Dry ice cryoamputation: a 12 after cryoablation therapy for prostatic cancer. Urology 1999;54:
year experience. J Vasc Surg 1985;2:812±16 295±9
38 Meijer S, Rahusen FD, Van der Plas LG. Palliative cryosurgery for
rectal carcinoma. Int J Colorect Dis 1999;14:177±80 43 Saliken JC, McKinnon G, Gray RR, et al. Liver cryosurgery with
curative intent: can we realize the promise? Can Assoc Radiologists J
39 Dennison AR, Paraskevopoulos JA, Kerrigan DD, et al. New thoughts
on the aetiology of haemorrhoids and the development of non-operative 1999;50:295±7
methods for their management. Minerva Chir 1996;51:209±16 44 Bickels J, Meller I, Shmookler BM, et al. The role and biology of
40 Maiwand MO. The role of cryosurgery in palliation of tracheo- cryosurgery in the treatment of bone tumours. A review. Acta Orthop
bronchial carcinoma. Eur J Cardio-Thorac Surg 1999;15:764±8 Scand 1999;70:308±15

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