Prig. Surg., vo1.14, pp. 136-159 (Karger, Basel 1975)
Cryosurgery JAMEs FRASER Department 0f Surgery, Southampton University Medical School, Southampton
Contents History Physical Properties Mechanisms of Freezing Injury Biological Effects of Cryosurgery Clinical Application Surface Tumours Oral and Maxí11ofacia1 Regions Neurosurgery Cryoprostatectomy Ophthalmology
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The application of very low temperatures to living tissues produces a complete and unselectíve destruction of the cells within the affected area. Its use in the treatment of disease is known as cryosurgery and it is recognised to have many advantages when compared with conventional methods of treatment. Haemostasis, anaesthesia, ease of control and the ability to produce absolute cell destruction are features which are not obtainable with other techniques while with modern instrumentation it is possible to quantify accurately and with confidence the volume of tissue destroyed during the procedure. This may be either to a predetermined amount or by continuous monitoring to an amount determined by the operator.
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Cryohaemorroidectomy Other Indications Future of Cryosurgery References
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The effects of cold were well known to surgeons in the 19th century and before, as both a form of physical trauma and as a palliative in painful conditions, but the first documented report on its use was made in 1851 by Dr. JAMES ARNOTT, the one-time Medical Superintendant of St. Helena [3]. Dr. ARNOTT described the direct application of a salt-ice mixture at about —20 0C in the treatment of a wide range of conditions and although most of them were nonspecific such as neuralgia, headache and pruritis they also included local advanced carcinoma of the cervix uteri and advanced breast cancer. His description indicated that although it was accepted that the disease was not cured there was a dramatic reduction in the discharge and bleeding from the surface of the tumour, a temporary regression in its size, and significant alleviation of pain. In spite of this early contribution the problems encountered in handling the cold materials were such that little interest was stimulated within the medical profession and it was not until more efficient and more practical materials and techniques were evolved that interest in therapeutic freezing was again stimulated. At first this was restricted to locally applied solid carbon dioxide and liquid nitrogen which were used to treat warts and small skin tumours but good results were claimed in terms of eradication and residual scarring. In 1961 Dr. IRvnvE COOPER of New York described a cryosurgery unit in which liquid nitrogen was used as the freezing agent [6]. The apparatus consisted primarily of a metal probe through which liquid nitrogen was circulated and which was itself vacuum-insulated except for the tip. The temperature could be controlled by interrupting the flow of the cooling agent but the tip could be accurately maintained at any temperature from 0 down to a —196 OC. The significance of this equipment was that cold could be safely applied to any part of the body to which the tip of the probe could be introduced and the tissue surrounding the probe could be independently frozen and destroyed. Furthermore, the cold could be applied for any length of time and its temperature could be controlled with remarkable accuracy. The first clinical application of this technique was in the field of neurosurgery, in the treatment of parkinsonism. It was soon recognised, however, that its special properties made it eminently suitable for use in other surgical fields as an alternative to surgical excision. It produced an absolute and unselective tissue destruction followed by aseptic necrosis, absorption of the dead tissue and a rapid epithelial cover of the resultant ulcer. There was virtually no bleeding within the area that was treated and
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History
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there was a discrete boundary between the destroyed tissue and the surrounding structures which were totally unaffected. This principle in which a liquid gas was circulated through a closed system has been the basis for the majority of cryosurgical units and various probe designs have been introduced for specific applications. Alternative instruments less complex and therefore less expensive employ the Joule-Thomson effect in which a compressed gas is allowed to expand suddenly through a small aperture with an accompanying and considerable drop in environmental temperature. The depth of cooling varies with the size of the aperture and the degree of compression of the gas and the resultant rate of expansion. In general using nitrous oxide at 2,500 lb/ßn2 temperatures in the region of —70 0C are attained, but in conjunction with some forms of microrefrigeration pre-cooling it is possible to obtain temperatures approximating to the liquid gas cryoprobes.
The process by which a cryolesion grows around the hemispherical tip of a standard cryoprobe is associated with local tissue temperatures and freezing rates which are directly related to and govern the rate of advance of the icewater boundary. In ideal circumstances, that is to say in tissue of uniform composition and thermal characteristics and with a uniform ambient temperature, the ultimate cryolesion assumes the shape of a sphere whose boundary remains equidistant from the tip of the probe after a state of thermodynamic equilibrium is attained between the temperature of the tip and the temperature within the surrounding tissues. Temperature measurements recorded along the radius of the sphere show that at this stage a thermal gradient exists which demonstrates a steep initial rise in temperature in the vicinity of the probe diminishing gradually to the freezing temperature of this tissue as the ice boundary is approached. From the ice boundary through the normal adjacent tissue the temperature gradient continues to rise possibly in a symmetrical pattern until the ambient temperature of the tissue is reached at a point 6-8 mm from the cryolesion edge (fig. 1). The growth of the cryolesion and its eventual size is directly related to a number of factors, the most significant of which are the probe size, its temperature, and the duration of the freeze. There is a direct relationship between the size of the lesion and both the size of the probe and its
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Physical Properties
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Freezing contours
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temperature while the relationship to the duration of the freeze is logarithmic during the period of maximum growth. In general the dimensions and the characters of cryolesions are constant for a single probe application and for a constant temperature and duration, though there may be minor variations in some body tissues. 80-900/0 of the freezing effect will be produced within a period of 15 min though the maximum effect may require at least 2 h of freezing [8]. Successive applications of identical freeze/thaw cycles at the same site will, however, alter significantly this performance. The rate of expansion of the ice water boundary through the tissues is accelerated with each successive freeze, and the volume of frozen tissue increases until a new maximum effect is obtained after the 5th-7th applications (fig. 2). This is almost twice the size of the maximum effect
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Fig.]. Temperature measurements recorded along the radius of a cryolesion during freezing and thawing.
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which can be produced by a single freeze of unlimited duration using the same probe and temperature and it appears that this multiple freeze phenomenon is related to the increased thermal conductivity of tissues previously stressed by the freezing injury [9]. Theoretical considerations would suggest that there are a number of additional variables related to the tissue to be frozen which could influence the size and the growth of the cryolesion. These variables include the thermal diffusivity, the osmolarity of the tissue and its ambient temperature.
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Fig.2. Effect of repetitive freeze-thaw cycles on the dimensions of the cryolesion (freezing for 1 min).
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In practice, however, with the possible exception of bone the tissues of the human body are relatively constant in their thermal properties and their influence on the performance of a cryoprobe is therefore negligible [3]. The one exception to this, however, is the presence of a major heat sink such as a large blood vessel. By constantly extracting cold from a specific area a major blood vessel may significantly influence the expansion of the cryolesion at that site, and until the vessel and its contents are frozen solid the expanding cryolesion will be visibly indented in the region of the vessel. The influence of ambient temperature has a further significance in that there is a 50/o increase in the dimensions of the iceball with each one-degree fall in ambient temperature. For this reason it is possible that a greater volume of tissue may be frozen by some means of pre-cooling tissues prior to the application of the probe.
The principle which governs cryosurgery is that living cells are at first injured and later die from the effects of the freezing injury and that this change is uniform throughout the tissues so treated. The mechanism of cell death is not fully understood but it is almost certainly induced by a combination of cryobiological effects [14]. (1) Extracellular ice crystals develop within the extracellular phase of the tissue when the freezing rate is slow. They are large and sharp and their effect on living cells is a mechanical disruption. Intracellular crystals appear when the freezing rate is rapid but seldom above a temperature about —80 0C. They appear to destroy the cell by disorganisation of the intracellular mechanisms. (2) The water content of the tissues, especially free extracellular water is utilised to form extracellular crystals. This produces a hyperosmolar state which extracts water from the intracellular phase and has the effect of inducing a toxic concentration of electrolytes which itself inflicts irreparable damage. (3) An alteration in pH and denaturation of lipid protein complexes occurs within the cell, both of which are incompatible with cell life. (4) Freezing produces vascular stasis in the small blood vessels partly by plasma escape and partly by obstruction to the feeding vessels. The effect of this is to initiate a process of ischaemic infarction. Evidence in favour of one of these causes of death in preference to the
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Mechanisms of Freezing Injury
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others has remained indefinite. Crystallisation can be demonstrated in a suitable histological preparation and there is little doubt that both intracellular osmotic tension and pH are altered. The rate and site of crystal formation in tissues is related to the solute concentration within the tissues, the freezing temperature and the freezing/thawing rates and it is the last of the three which is of most significance. Α process in which tissues are frozen slowly is probably the most lethal to cells, and conversely a rapid freeze is most likely to be associated with a proportional survival. However, it is well known that cells in suspension may survive cooling to temperatures from —70 to 120 OC and tumour cells such as sarcoma 37 can retain a proportional survival after sudden immersion in liquid nitrogen at —196 OC [12]. It is apparent, therefore, that individual cells vary in their ability to withstand thermal stresses, and some cells faced with temperature insults are capable of undergoing a protective morphological reaction. Furthermore, it can be shown by cell suspension survival experiments that cells of different structure vary significantly in their resistance to different freezing rates. It is all the more confusing, therefore, that the temperature gradients that occur within the iceball during a single freeze/thaw cycle using a standard cryoprobe suggest that in some areas the parameters are not dissimilar to those observed in the cell suspension experiments [18]. That is to say the local changes in no way differ from those associated with a significant cell survival, and it must therefore be assumed that a proportion of the cells survive the initial thermal injury [7]. This is obviously not compatible with the clinical observations that the final picture is that of uniform cell death. It appears likely, therefore, and investigations tend to confirm that there are two phases to the freezing injury. There is an initial phase but within a few hours of this direct thermal injury there is the second phase, namely ischaemic infarction. The evidence to support this hypothesis that cellular anoxia is the ultimate lethal mechanism is largely circumstantial, namely the histological changes which will be discussed later, the survival of transplanted cells taken from a cryolesion immediately after thawing and the almost complete absence of surviving cells when the tissue is sampled 24 h after freezing [8]. More direct evidence is found in circulation experiments examining the uptake of radioactive xenon and in the intravascular injection of carbon particles [20]. Both of these tend to confirm that the microcirculation, initially patent in the first hour after the freeze is totally obliterated in the succeeding hours.
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Fig. 3. Macroscopic appearance of cryolesion in rat liver 5 min after freeze-thaw showing characteristic sharply demarcated dark areas. Fig. 4. Macroscopic appearance of cryolesion in rat liver 5 weeks after freeze-thaw, showing loss of tissue and residual fibrous scar.
The immediate visible effect of the application of a cryoprobe to tissues is the formation of a sharply demarcated iceball which on thawing becomes dark red and haemorrhagic (fig. 3). During the ensuing 24 h the lesion starts to become gradually but increasingly mottled with grey patches. The lesion itself gradually reduces in size, the limits of the damaged area being smaller than the original visible iceball and by direct measurement it has been found that the periphery of the zone corresponds to the point in the iceball which has fallen to a temperature of —15 0C. By the 3rd day after the freeze the mottling process has spread to involve the whole area which gradually becomes separated as a slough. This progressively shrinks and finally disappears as healing progresses from the margins of the lesion (fig. 4). Infection is not observed and there is little evidence of an inflam-
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Biological Effects of Cryosurgery
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b
matory reaction in the surrounding tissues. By the 4th week after the freeze there is little left other than a small fibrous scar. Histological changes are equally dramatic, the earliest appearance on light microscopy being that of uniformly altered cells sharply demarcated from the surrounding normal tissues. The dark red appearance which is noticeable on thawing is apparently caused by vascular dilatation and by an intense congestion of the small vessels with erythrocytes Immediate fixation of the frozen area shows typical ice crystal formation most obvious towards the periphery of the lesion. Initially there is no clear intermediate zone between the frozen and the normal tissues, but within 30 min there is a distinct band some 10-30 cells broad separating the injured from the normal tissue (fig. 5). This corresponds exactly to the periphery of the damaged zone. The ultimate fate of this intermediate area is uncertain. It becomes progressively less distinct but simultaneously and at an early
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Fig. 5. Light-microscopic appearance showing the typical junction zone at the periphery of the cryolesion. a 24 h after freeze. x 10. b Six days after freeze. x 10.
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stage there is peripheral fibroblastic activity. Thereafter it appears to pass through a phase of organisation until it finally forms a distinct fibrous capsule to the lesion. Within the injured tissue there is evidence of cellular fragmentation and a marked increase of the intercellular spaces, much of this space being filled with extravasated erythrocytes. At this stage the cells are shrunken with progressive pyknosis and the intracellular details obscured. Thereafter the changes do not differ greatly from those associated with an ischaemic infarct. The dilatation and sludging progresses to thrombus formation in vessels and ultimately disintegration of the vessel wall. There is increasing margination and emigration of cells through the wall with a rapidly increasing cellular infiltration composed mainly of polymorphs, and with lymphocytes and plasma cells confined primarily to the margin of the lesion. Throughout this process the tissues adjacent to the frozen area show little morphological change and by the time of organization the surrounding structures are indistinguishable from normal. Tissue interphases are no barrier to the development of the freezing boundary and the changes that have been described occur in all tissues. Smaller blood vessels are obstructed by thrombus formation at an early stage. Large blood vessels behave in an interesting manner in that although there is the anticipated cell death in all layers, the integrity and strength of the vessel wall is unaffected largely as a result of the elastic tissue component. Blood flow returns on thawing in all but the smaller vessels and there is no evidence of late aneurysm formation. Similarly bone may be incorporated into an iceball and although the cellular element is destroyed it retains its structural integrity and strength and is ultimately recolonised with its normal cellular components. The appearances on electron microscopy are as in the light microscopy, somewhat nonspecific. The first visible changes appear at 15 min after the freeze with early crenation of the nuclei and mitochondrial swelling (fig. 6). At first the only cytoplasmic change is an occasional vacuolation. Throughout the 1st h there is dilatation of the endoplasmic reticulin with loss or fragmentation of the mitochondrial cristae and the appearance of grey areas and some dark bodies within the cytoplasm. The nuclear membrane remains intact up to 4 h, but by 6 h nuclei are barely distinguishable and by 12 h all cells appear dead (fig. 7). Although the ultimate pattern is of total and uniform cell death, electron microscopy does demonstrate that individual cells are not necessarily affected to the same extent or at the same rate as their immediate neighbours. The changes which follow cryosurgical injury to peripheral nerves
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Fig. 6. Electron-microscopic appearance 15 min after freeze showing early changes of nuclear crenation and mitochondrial swelling.
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Fig. 7. Electron-microscopic appearance 6 h after freeze showing gross nuclear fragmentation.
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are quite characteristic [5]. Cellular damage appears to be complete after 24 h and involves all components of the nerves. The sheath and axon are devitalised and there follows Wallerian and retrograde degeneration. The connective tissue of the nerve sheath, however, retains its integrity and remains as a continuous collagenous tube without evidence of inflammatory reaction. Provided the ganglion cell is undamaged revitalisation begins about 12 days after the injury and normal nerve architecture and function is complete within 30 days.
The ability to destroy all tissue regardless of its type means that freezing is particularly indicated in the treatment of tumours but its facility to be applied to any part of the body to which the probe can be introduced infers that it can destroy circumscribed volumes of tissue in otherwise inaccessible situations. Furthermore, by its accuracy of control it may be used to destroy predetermined volumes of tissue regardless of the dimensions. The constraints to its use at this stage in its development are restricted to the practical problems of identifying with accuracy the extent of the destruction, especially in malignant disease and in inaccessible sites. However, on the understanding that the limits of the cryolesion are at —15 0C and that this is from 1 to 2 mm from the edge of the visible or palpable iceball it is possible to assess either by sight, by touch or by the use of implanted thermocouples the likely extent of the zone of destruction. Thermocouples are usually designed in the form of a needle with a single temperature sensitive copper-constantan element at its end. Although efficient in determining the temperature at a single point, difficulty may be experienced in siting the tip and thereby in identifying the point. Alternatively a multiple thermocouple of the Benn-Merry type can be used. This carries multiple elements along its length and detects temperature changes at identifiable points during the iceball growth [4]. Since in some situations overfreezing is as undesirable as underfreezing the technique using thermocouples is either to calculate the required size of iceball before operation and to stop freezing at the predetermined point or to identify the temperature changes in the tissue outside the iceball. The latter technique depends on the principle that a temperature gradient develops well in advance of the expanding ice-water boundary [8].
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Clinical Application
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b Fig.8. a Locally extensive carcinoma of the breast. b The entire tumour mass is encompassed by repeated and multiple applications.
Freezing is commonly used for primary skin tumours or metastatic deposits in or immediately beneath and involving the skin, but it can also be used to treat any surface tumour such as within the nasopharynx, the alimentary tract, the bladder or the peritoneal cavity. Α small skin tumour up to 4-5 cm in diameter can be completely obliterated and the results in terms of cosmetic appearance are unequalled by other methods. Unfortunately, when the probe is applied to the surface the resultant iceball will
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Surface Tumours
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take the form of a hemisphere while the malignant tumour with its deep extension is more comparable in shape to the iceberg. For this reason it is usually necessary to freeze a large area of skin to encompass the entire growth. As an example cryosurgery is ideally applicable to recurrent chest wall and axillary breast cancer. Relatively large tumour masses can be destroyed especially if a technique of repetitive freeze is used the resultant ulcer epithelialising rapidly (fig. 8, 9). In practice it is preferable to encompass the entire tumour mass by multiple applications on the first occasion even though this does infer an overfreeze and destruction of
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Fig. 9. Basal cell carcinoma of the cheek. a Before freezing. b Six weeks after a single freeze.
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normal surrounding tissue. The alternative technique is to destroy the greater part of the tumour on the first application, further freezes being required for residual tumour. In either circumstance it is important that there should be the widest and closest possible contact between the probe and the target tissue. The property of cryoadhesion ensures that provided the surfaces are moist there will be a firm bond, but it must be emphasised that this feature of freezing occurs maximally if the probe is applied when warm and cooled in that position. If it is cooled to —80 0C or below before being applied the adhesion is weak. In surface tumours and elsewhere the contact can be increased by inserting the probe tip directly into the tumour mass. Although in theory this trauma is capable of releasing cancer cells into the circulation this is probably irrelevant in most circumstances. It has the additional advantage of allowing the iceball to be sited in an optimal position within the tumour mass. Tumours which lie below healthy skin or other surface epithelium can be frozen by applying the probe directly to
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Fig.10. Chest wall recurrence of carcinoma of the breast. Cryoprobe applied directly to the tumour mass through a small skin incision.
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the overlying skin. The frozen skin will die with the tumour but the resultant ulcer heals rapidly and completely. The alternative technique which is probably preferable is to incise the skin and to apply the probe directly to the tumour. The undamaged skin flaps heal satisfactorily even though they lie on dead tumour tissue (fig. 10). Other surface tumours such as basal cell carcinoma, squamous carcinoma and malignant melanoma are equally suitable for cryocoagulation though in primary tumours of this nature it is essential that adequate destruction be obtained at the first sitting. Where there is no histological confirmation of the diagnosis a biopsy can be taken from the frozen tissue without bleeding, or fear of dissemination. The piece of tissue removed is managed while still solid as a typical frozen section. Anaesthesia is frequently unnecessary in the treatment of surface tumours but there are occasions in which the patient experiences a frostbite type of discomfort and local anaesthesia with mild sedation is usually adequate analgesic.
Cryosurgery has many advantages in the management of simple lesions of the oral cavity. Granulomata, papillomata, fibrous epulides and hyperplastic lesions are obvious examples especially where orthodox excision has recognised disadvantages. Surface changes, such as leukoplakia, can be totally eradicated and if a purpose-designed probe tip with a relatively large surface area is used the depth of destruction need not be excessive. Tonsillectomy has been carried out with great success using a cryoprobe. Vora LEDEN [19] comments on the special value of this technique when the surgical problem is complicated by a blood dyscrasia such as haemophilia, Von Willebrand's disease and thrombocytopaenia [10]. The morbidity is minimal in all cases and there are no specific contraindications. Vascular lesions such as oral or facial angioma, haemangioma and lymphangioma form an ideal group for control by cryosurgery [17]. The small lesions are usually manageable by a single freeze but extensive or deep involvement probably requires several applications. Because of the vascular nature of the tumour and the heat sink effect of the major feeding vessels this is one of the occasions in which the more powerful liquid nitrogen cryoprobe must be used. Excellent cosmetic results may be obtained though on occasions there may be slight fibrosis and in the typical port wine stain the overlying skin seldom returns to normal.
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Oral and Maxillofacial Regions
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In the management of malignant tumours of the oropharynx Posωτnο [16] has shown that cryosurgery has advantages over alternative treatments. With care the tumour can be totally eradicated without scarring or loss of the vermillion border on the lip and the capacity of this method for controlling the dissemination of tumour cells by immobilising them within the iceball is an obvious advantage. In these circumstances, as in surface skin tumours, overfreezing is essential. Α rapid freeze to temperatures below —80 0C is almost certainly required and it is an indication for a liquid nitrogen probe rather than the less powerful Joule-Thomson equipment. It is a further indication for repetitive freeze rather than a single application. Malignant tumours invading neighbouring structures can be frozen without hazard, for example, to the underlying bony structures, there being no likelihood of sequestrum formation or of painful persistent ulceration. Finally the larger primary or recurrent oral and nasopharyngeal cancers are ideally treated by cryosurgery. In these circumstances it is unlikely that a complete control can be obtained at one sitting, but the resultant benefits in relief of pain, control of surface discharge and haemorrhage are most gratifying and there is no contraindication to repeated applications. In extensive tumours the possibility of freezing uninvolved structures even within the cranial cavity is disregarded. Cryosurgery has many advantages in the management of malignant lesions of the oropharynx and nasopharynx. The probe can usually be applied even in the most inaccessible sites. It can be used repeatedly even in the poor risk patient and there is much less disability in the postoperative care period. The structure and function of the normal tissues, especially the bony facial skeleton, is retained. Complications are rare. Finally, it may be used in the presence of heavy surface infection and even in radioresistent tumours. On occasions the regression of tumour tissue is striking, but even in palliative circumstances the relief of symptoms can be dramatic. Obviously the tumours that respond most favourably to freezing are the locally malignant varieties, such as the adenoid cystic carcinoma and the basal cell carcinoma, but the only contraindication is evidence of rapidly advancing, widespread disease in which the patient may not survive long enough to obtain the maximum benefit from the local treatment. It must therefore be remembered that a full epithelial cover may be delayed for up to 6 weeks after the freeze.
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Cryosurgical equipment was first designed for use in neurosurgery and it was obviously in this field that most of the pioneer work on cryogenic techniques was undertaken. Its particular properties of accuracy of control, haemostasis and the creation of a hard iceball in friable tissue made it eminently suitable for brain surgery. In soft tumours the probe is applied at craniotomy and the iceball is allowed to grow until it encompasses the tumour growth, which is then separated by blunt dissection and without difficulty from the normal surrounding brain tissue. Alternatively, since it is known that the frozen tissue will die the tumour can be allowed to thaw and left in situ. Initially there is considerable local oedema but thereafter the degenerative changes progress without affecting the surrounding structures. The possibility of an initial reversible lesion in which the probe is first applied at a temperature cold enough to paralyse the affected cells but well above their freezing point is an additional attraction. In parkínsonísm and choreoathetosis, the specific areas within the brain responsible for these movements can be identified by inserting a small 2-mm probe under local anaesthesia. When sited in roughly the correct area the temperature is gradually lowered and the brain tissue cooled. The subsequent effects on the patient's symptoms indicates whether the probe is correctly situated. If the tremor is insufficiently corrected the probe is withdrawn and repositioned without permanent injury. When the position has been confirmed the surgeon reduces the temperature to a lethal degree and destroys with accuracy the relevant small groups of cells. A similar reversible technique can be used to identify and to destroy pain-carrying fibres in the spinothalamic tract of the spinal cord in patients with painful irremovable malignant disease within the pelvis, or lower extremity. In both the intracerebral and spinal cord situations a stereotactíc technique is used in preference to an open operation. Destruction of the pituitary by cryohypophysectomy is indicated in patients with primary tumours of the pituitary such as the acidophiladenoma, in patients with breast cancer and in certain cases of diabetes mellitus in which it is known that pituitary ablation may result in a regression of the associated retínopathy. In this technique a trocar and cannula are inserted through the nasopharynx and enter the pituitary fossa through the sphenoid, the trocar is withdrawn and a small probe passed down the cannula. The position of the cannula is usually controlled by a stereotactic harness, though a free-hand technique with continuous radio-
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logical monitoring is equally effective. The pituitary and its stalk can be destroyed totally without difficulty but care must be taken to avoid damage to neighbouring structures, especially the optic chiasma. In these circumstances some means of predicting the size of the iceball is essential since the lesion cannot be assessed visibly or by palpation. The technique of cryohypophysectomy is further influenced by the presence of considerable heat sinks in the form of internal carotid arteries, and allowance has to be made for this factor in the prediction. For this reason and the fact that the 2-mm probe is relatively low-powered it is usual for two small symmetrical iceballs to be created on either side of the pituitary fossa rather than one single all-encompassing lesion. There are few complications following cryohypophysectomy. Rhinorrhoea may occur for a few days but it is less significant that after pituitary implantation, meningitis has not been reported, though it is customary to give prophylactic antibiotics. Diabetes insipidus may occur. In general the technique is less efficient than an open operation but it is safe, effective and is ideally suited to high-risk patients.
The usual cryoprobe is designed with a non-insulated tip for terminal freezing but special purpose probes have been designed for specific operative procedures. One of these has a curved end similar in shape to a coudé catheter with a pre-terminal non-insulated segment. This instrument can be introduced into the prostatic urethra and by creating a lemonshaped iceball over the non-insulated segment it can freeze an equivalent shape and volume of prostatic tissue. Cryoprostatectomy is more comparable to the transurethral resection than to an open operation in that it clears a passage through the prostatic urethra rather than ablating the entire adenomatous tissue. The extent of the iceball can be determined either by thermocouples implanted through the capsule of the prostate or by the more crude but equally effective methods of palpating the iceball with a finger in the rectum. The frozen segment of the gland undergoes the usual ischaemic necrosis and the slough is either passed per urethra or gradually disappears in about 3 weeks. There is no significant haemorrhage during or following the procedure but an indwelling catheter must be left in position for up to 10 days. Complications do occur, including post-operative urinary infection, epididymo orchitis, penile oedema, and osteitis pubis. In general,
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however, the results of treatment are satisfactory with early painless micturition, no residual urine, and an adequate return to normal control [11]. This technique is obviously no better than the standard operations for the fit patient with a simple prostatic hyperplasia, but it is especially indicated for prostatic carcinoma and for patients suffering from an associated disease, such as the respiratory cripple unfit for general anaesthesia [17]. It is also ideally suited for patients on anticoagulant treatment or suffering from a bleeding disease such as haemophilia. Although there may be residual adenomatous tissue which could recur the extent of the trauma is such that repeated cryoprostatectomy is a quite acceptable form of management in high-risk patients. Ophthalmology The property of freezing that is most utilised in ophtalmology is that of cryoadhesion, namely, the fact that any metal object, when frozen, will adhere firmly and permanently to all damp living tissues. The removal of the opaque lens from the eye in a cataract operation is greatly facilitated by placing a small relatively low-powered cryoprobe in contact with the periphery of the lens. A bond is formed between the probe and the lens which is strong enough to allow a gentle but controlled manipulation and extraction. In other ophthalmological disease local freezing may also be of value, for example to produce a minute point of tissue coagulation through the sclera as part of the fixation of a detached retina or to control inflammatory disease.
The indications for cryosurgery in gynaecology are not dissimilar from the indications elsewhere, namely, to destroy localised benign disease and to control invasive tumours, especially when alternative methods are not available or practicable. There are two particular fields, however, in which the technique has special merit. In disease of the cervix, such as the small in-situ carcinoma and cervical erosions a specially shaped cryoprobe can be inserted into the external os. The resultant iceball destroys the local disease but the absence of local scarring prevents injury or stensis of the cervical canal. Epithelial cover occurs rapidly and is complete even in the
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Gynaecology
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presence of extensive and deep erosions with gross superlicial infection. Freezing may also be used to remove labial and perineal venereal warts and if used correctly is highly successful. It is an interesting application of the technique, however, since viruses are peculiarly resistant to rapid freezing and low temperatures, and unlike other disease relatively mild cooling is more effective than the usual rapid freeze. Alternatively, repeated exposures can be successful in resistant cases. Cryohaemorroidectomy A somewhat specific use of cryosurgery is in the management of haemorrhoids. In this situation the three primary pile masses are individually frozen to create three separate iceballs. Each haemorrhoid is in turn withdrawn through the anal canal and the cryoprobe is laid along its surface. The tissue undergoes the usual aseptic necrosis with separation of the slough and early epithelial cover. The complete process may take up to 6 weeks and is accompanied by considerable local discharge but there is no discomfort, no bleeding and the final result is cosmetically and functionally most satisfactory. The advantage of this technique is that it requires minimal hospitalisation, it can be undertaken with minimal anaesthesia and is eminently suitable as outpatient treatment or for the high-risk patient. Other Indications Cryosurgery has been used in many other circumstances varying from the treatment of verrucae to the obliteration in situ of hepatic metastases or as an adjuvant to a partial hepatectomy and in the treatment of localised tumours within the abdominal cavity and in the lungs. In each of these situations the destructive capabilities ensure that the frozen tissue is destroyed but its use is only of significance if the tumour can be totally encompassed by the iceball.
The cryoprobe is regarded as a sophisticated instrument of destruction and has an undoubted value in its own particular field. It is likely that in
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Future of Cryosurgery
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the future its use will be widened to include new sites within the body and the treatment of a wider range of diseases. Improved technique may result in larger volumes of tissue destruction and a greater understanding of the nature of the destructive agent will result in a finer control of this destruction and a greater ease of predictability in concealed sites. Recently it has been suggested that within a tumour destroyed by freezing there is a release of tissue proteins which acquire new antigenic properties or of pre-existing but unavailable antigens [15]. The result of this is the development of an immune response to the target tissue and probably related directly to the freezing injury. It is accepted that this release of antigenic substance occurs during the relatively slow thawing period rather than in the initial freeze and as such differs from the effects of other forms of tissue injury. The first report of this antigenic response was made by Asux et al. [1, 2], who identified specific autoantibodies in the male rabbit following cryocoagulatíon of the accessory gland of reproduction. These investigations paralleled a report in which metastatic deposits of prostatic carcinoma were seen to regress following repeated cryocoagulation of the prostatic primary. More recently antibody responses have been demonstrated after treatment of rectal carcinoma, malignant melanoma and basal cell carcinoma. These isolated reports are suggestive of an acquired response against the injured tissue but they are insufficient to allow us to assume that there is now firm evidence of a clinically significant immune response against malignant tumours. Ø the other hand should this phenomena be substantiated its potential application to cancer therapy would be a most exciting prospect.
1 ABLIN, R. J. ; SολνΕs, W. Α., and GoinoR, M. J. : Clinical and experimental considerations of the immunological response to prostatic and other accessory glands of reproduction. Urol. int. 25: 511 (1970). 2 ABLIN, R. J. ; Somas, W. Α., and GoinoR, M. J. : Elution of in vivo bound antiprostatic epithelial antibodies following multiple cryotherapy of carcinoma of prostate. Urology 11: 276 (1973). 3 ARNorr, J.B.: On the treatment of cancer by the regulated application of an anaesthetic temperature (Churchill, London 1851). 4 Bau, D.N. and MERRY, J.J.: Α multisensor cryogenic temperature probe. Proc. int. cryogen. Eng. Cont. 4: 375 (1972). 5 CARTER, D.C. ; LEE, P. W. R. ; Giri, W., and Joηνsrοκ, R. J.: The effects of cryosurgery on peripheral nerve function. AØ. R. Coll. Surg. 17: 25 (1972).
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References
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Prof. J. FRASØ, Professor of Surgery, Faculty of Medicine, Surgical Division, The University of Southampton, Fanshawe Street, Southampton S09 4ΡΕ (England)
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6 COOPER, I. S. and LEE, A. St. J. : Cryostatic coagulation; a system for producing a limited controlled region of cooling or freezing of biological tissues. J. nerv. ment. Dis. 133: 259 (1961). 7 FARκπκτ, J. : Some mechanisms of freezing injury. Proc. Int. Congr. Cryosurg, p.23 (1972). 8 Gn L, W. ; DA COSTA, J., and FRASER, J. : The control and predictability of a cryolesion. Cryobiology 6: 347 (1970). 9 GILL, W. ; FRASER, J., and CARTER, D. C. : Repeated freeze/thaw cycles in cryosurgery. Nature, Lond. 219: 410 (1968). 10 GILL, W. ; FRASER, J. D. ; LoNG, W., and LEE, P. W. R.: Cryosurgery for neoplasia. Br. J. Surg. 57: 494 (1970). 11 GoiioR, Μ. J. ; SoAias, W.A., and SmiLlAi, S.: Cryosurgical treatment of the prostate. Investie Urol. 3: 372 (1966). 12 LEmo, S.P. ; FARRπκΤ, J. ; ΜλzuR, P.; Ηλννλ, M.G., and SMITH, L.H.: Effects of freezing marrow stem cell suspension. Cryobiology 6: 315 (1970). 13 MARSHALL, A.: Cryogenic surgery of the prostate. Proc. R. Soc. Med. 61: 1139 (1968). 14 MERYMAN, H.T.: Cryobiology, pp.2-91 (Academic Press, New York 1966). 15 MYERS, R. S. ; Hλµµονn, W. G., and ΚΕΤCHΑM, A. : Tumour specific transplantation immunity after cryosurgery. J. Surg. Inc. 1: 241 (1969). 16 PoswxLLo, D. : Cryosurgery and electrosurgery compared in the treatment of experimentally induced oral carcinoma. Br. dent. J. 131: 347 (1971). 17 PoswτLLO, D. : Comparative study in the effects of electrosurgery and cryosurgery in the management of benign oral lesions. Br. J. oral Surg. 9: 1 (1971). 18 SMιrκ, J. J. and FRASER, J. An estimation of tissue damage and thermal history in the cryolesion. Cryobiology 11: 139 (1974). 19 LEDEN, Η. voi: Current trends in cryosurgery of the head and neck Cryosurgery 1: 160 (1968). 20 WHAArAKER, D. K.: Ultrastructural changes in oral epithelium following cryogenic surgery. J. dent. Res. 48: 118 (1969).
Cryosurgery JAMEs FRASER Department 0f Surgery, Southampton University Medical School, Southampton
Contents History Physical Properties Mechanisms of Freezing Injury Biological Effects of Cryosurgery Clinical Application Surface Tumours Oral and Maxí11ofacia1 Regions Neurosurgery Cryoprostatectomy Ophthalmology
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The application of very low temperatures to living tissues produces a complete and unselectíve destruction of the cells within the affected area. Its use in the treatment of disease is known as cryosurgery and it is recognised to have many advantages when compared with conventional methods of treatment. Haemostasis, anaesthesia, ease of control and the ability to produce absolute cell destruction are features which are not obtainable with other techniques while with modern instrumentation it is possible to quantify accurately and with confidence the volume of tissue destroyed during the procedure. This may be either to a predetermined amount or by continuous monitoring to an amount determined by the operator.
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Cryohaemorroidectomy Other Indications Future of Cryosurgery References
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The effects of cold were well known to surgeons in the 19th century and before, as both a form of physical trauma and as a palliative in painful conditions, but the first documented report on its use was made in 1851 by Dr. JAMES ARNOTT, the one-time Medical Superintendant of St. Helena [3]. Dr. ARNOTT described the direct application of a salt-ice mixture at about —20 0C in the treatment of a wide range of conditions and although most of them were nonspecific such as neuralgia, headache and pruritis they also included local advanced carcinoma of the cervix uteri and advanced breast cancer. His description indicated that although it was accepted that the disease was not cured there was a dramatic reduction in the discharge and bleeding from the surface of the tumour, a temporary regression in its size, and significant alleviation of pain. In spite of this early contribution the problems encountered in handling the cold materials were such that little interest was stimulated within the medical profession and it was not until more efficient and more practical materials and techniques were evolved that interest in therapeutic freezing was again stimulated. At first this was restricted to locally applied solid carbon dioxide and liquid nitrogen which were used to treat warts and small skin tumours but good results were claimed in terms of eradication and residual scarring. In 1961 Dr. IRvnvE COOPER of New York described a cryosurgery unit in which liquid nitrogen was used as the freezing agent [6]. The apparatus consisted primarily of a metal probe through which liquid nitrogen was circulated and which was itself vacuum-insulated except for the tip. The temperature could be controlled by interrupting the flow of the cooling agent but the tip could be accurately maintained at any temperature from 0 down to a —196 OC. The significance of this equipment was that cold could be safely applied to any part of the body to which the tip of the probe could be introduced and the tissue surrounding the probe could be independently frozen and destroyed. Furthermore, the cold could be applied for any length of time and its temperature could be controlled with remarkable accuracy. The first clinical application of this technique was in the field of neurosurgery, in the treatment of parkinsonism. It was soon recognised, however, that its special properties made it eminently suitable for use in other surgical fields as an alternative to surgical excision. It produced an absolute and unselective tissue destruction followed by aseptic necrosis, absorption of the dead tissue and a rapid epithelial cover of the resultant ulcer. There was virtually no bleeding within the area that was treated and
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History
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there was a discrete boundary between the destroyed tissue and the surrounding structures which were totally unaffected. This principle in which a liquid gas was circulated through a closed system has been the basis for the majority of cryosurgical units and various probe designs have been introduced for specific applications. Alternative instruments less complex and therefore less expensive employ the Joule-Thomson effect in which a compressed gas is allowed to expand suddenly through a small aperture with an accompanying and considerable drop in environmental temperature. The depth of cooling varies with the size of the aperture and the degree of compression of the gas and the resultant rate of expansion. In general using nitrous oxide at 2,500 lb/ßn2 temperatures in the region of —70 0C are attained, but in conjunction with some forms of microrefrigeration pre-cooling it is possible to obtain temperatures approximating to the liquid gas cryoprobes.
The process by which a cryolesion grows around the hemispherical tip of a standard cryoprobe is associated with local tissue temperatures and freezing rates which are directly related to and govern the rate of advance of the icewater boundary. In ideal circumstances, that is to say in tissue of uniform composition and thermal characteristics and with a uniform ambient temperature, the ultimate cryolesion assumes the shape of a sphere whose boundary remains equidistant from the tip of the probe after a state of thermodynamic equilibrium is attained between the temperature of the tip and the temperature within the surrounding tissues. Temperature measurements recorded along the radius of the sphere show that at this stage a thermal gradient exists which demonstrates a steep initial rise in temperature in the vicinity of the probe diminishing gradually to the freezing temperature of this tissue as the ice boundary is approached. From the ice boundary through the normal adjacent tissue the temperature gradient continues to rise possibly in a symmetrical pattern until the ambient temperature of the tissue is reached at a point 6-8 mm from the cryolesion edge (fig. 1). The growth of the cryolesion and its eventual size is directly related to a number of factors, the most significant of which are the probe size, its temperature, and the duration of the freeze. There is a direct relationship between the size of the lesion and both the size of the probe and its
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Physical Properties
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Freezing contours
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temperature while the relationship to the duration of the freeze is logarithmic during the period of maximum growth. In general the dimensions and the characters of cryolesions are constant for a single probe application and for a constant temperature and duration, though there may be minor variations in some body tissues. 80-900/0 of the freezing effect will be produced within a period of 15 min though the maximum effect may require at least 2 h of freezing [8]. Successive applications of identical freeze/thaw cycles at the same site will, however, alter significantly this performance. The rate of expansion of the ice water boundary through the tissues is accelerated with each successive freeze, and the volume of frozen tissue increases until a new maximum effect is obtained after the 5th-7th applications (fig. 2). This is almost twice the size of the maximum effect
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Fig.]. Temperature measurements recorded along the radius of a cryolesion during freezing and thawing.
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which can be produced by a single freeze of unlimited duration using the same probe and temperature and it appears that this multiple freeze phenomenon is related to the increased thermal conductivity of tissues previously stressed by the freezing injury [9]. Theoretical considerations would suggest that there are a number of additional variables related to the tissue to be frozen which could influence the size and the growth of the cryolesion. These variables include the thermal diffusivity, the osmolarity of the tissue and its ambient temperature.
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Fig.2. Effect of repetitive freeze-thaw cycles on the dimensions of the cryolesion (freezing for 1 min).
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In practice, however, with the possible exception of bone the tissues of the human body are relatively constant in their thermal properties and their influence on the performance of a cryoprobe is therefore negligible [3]. The one exception to this, however, is the presence of a major heat sink such as a large blood vessel. By constantly extracting cold from a specific area a major blood vessel may significantly influence the expansion of the cryolesion at that site, and until the vessel and its contents are frozen solid the expanding cryolesion will be visibly indented in the region of the vessel. The influence of ambient temperature has a further significance in that there is a 50/o increase in the dimensions of the iceball with each one-degree fall in ambient temperature. For this reason it is possible that a greater volume of tissue may be frozen by some means of pre-cooling tissues prior to the application of the probe.
The principle which governs cryosurgery is that living cells are at first injured and later die from the effects of the freezing injury and that this change is uniform throughout the tissues so treated. The mechanism of cell death is not fully understood but it is almost certainly induced by a combination of cryobiological effects [14]. (1) Extracellular ice crystals develop within the extracellular phase of the tissue when the freezing rate is slow. They are large and sharp and their effect on living cells is a mechanical disruption. Intracellular crystals appear when the freezing rate is rapid but seldom above a temperature about —80 0C. They appear to destroy the cell by disorganisation of the intracellular mechanisms. (2) The water content of the tissues, especially free extracellular water is utilised to form extracellular crystals. This produces a hyperosmolar state which extracts water from the intracellular phase and has the effect of inducing a toxic concentration of electrolytes which itself inflicts irreparable damage. (3) An alteration in pH and denaturation of lipid protein complexes occurs within the cell, both of which are incompatible with cell life. (4) Freezing produces vascular stasis in the small blood vessels partly by plasma escape and partly by obstruction to the feeding vessels. The effect of this is to initiate a process of ischaemic infarction. Evidence in favour of one of these causes of death in preference to the
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others has remained indefinite. Crystallisation can be demonstrated in a suitable histological preparation and there is little doubt that both intracellular osmotic tension and pH are altered. The rate and site of crystal formation in tissues is related to the solute concentration within the tissues, the freezing temperature and the freezing/thawing rates and it is the last of the three which is of most significance. Α process in which tissues are frozen slowly is probably the most lethal to cells, and conversely a rapid freeze is most likely to be associated with a proportional survival. However, it is well known that cells in suspension may survive cooling to temperatures from —70 to 120 OC and tumour cells such as sarcoma 37 can retain a proportional survival after sudden immersion in liquid nitrogen at —196 OC [12]. It is apparent, therefore, that individual cells vary in their ability to withstand thermal stresses, and some cells faced with temperature insults are capable of undergoing a protective morphological reaction. Furthermore, it can be shown by cell suspension survival experiments that cells of different structure vary significantly in their resistance to different freezing rates. It is all the more confusing, therefore, that the temperature gradients that occur within the iceball during a single freeze/thaw cycle using a standard cryoprobe suggest that in some areas the parameters are not dissimilar to those observed in the cell suspension experiments [18]. That is to say the local changes in no way differ from those associated with a significant cell survival, and it must therefore be assumed that a proportion of the cells survive the initial thermal injury [7]. This is obviously not compatible with the clinical observations that the final picture is that of uniform cell death. It appears likely, therefore, and investigations tend to confirm that there are two phases to the freezing injury. There is an initial phase but within a few hours of this direct thermal injury there is the second phase, namely ischaemic infarction. The evidence to support this hypothesis that cellular anoxia is the ultimate lethal mechanism is largely circumstantial, namely the histological changes which will be discussed later, the survival of transplanted cells taken from a cryolesion immediately after thawing and the almost complete absence of surviving cells when the tissue is sampled 24 h after freezing [8]. More direct evidence is found in circulation experiments examining the uptake of radioactive xenon and in the intravascular injection of carbon particles [20]. Both of these tend to confirm that the microcirculation, initially patent in the first hour after the freeze is totally obliterated in the succeeding hours.
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Fig. 3. Macroscopic appearance of cryolesion in rat liver 5 min after freeze-thaw showing characteristic sharply demarcated dark areas. Fig. 4. Macroscopic appearance of cryolesion in rat liver 5 weeks after freeze-thaw, showing loss of tissue and residual fibrous scar.
The immediate visible effect of the application of a cryoprobe to tissues is the formation of a sharply demarcated iceball which on thawing becomes dark red and haemorrhagic (fig. 3). During the ensuing 24 h the lesion starts to become gradually but increasingly mottled with grey patches. The lesion itself gradually reduces in size, the limits of the damaged area being smaller than the original visible iceball and by direct measurement it has been found that the periphery of the zone corresponds to the point in the iceball which has fallen to a temperature of —15 0C. By the 3rd day after the freeze the mottling process has spread to involve the whole area which gradually becomes separated as a slough. This progressively shrinks and finally disappears as healing progresses from the margins of the lesion (fig. 4). Infection is not observed and there is little evidence of an inflam-
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Biological Effects of Cryosurgery
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b
matory reaction in the surrounding tissues. By the 4th week after the freeze there is little left other than a small fibrous scar. Histological changes are equally dramatic, the earliest appearance on light microscopy being that of uniformly altered cells sharply demarcated from the surrounding normal tissues. The dark red appearance which is noticeable on thawing is apparently caused by vascular dilatation and by an intense congestion of the small vessels with erythrocytes Immediate fixation of the frozen area shows typical ice crystal formation most obvious towards the periphery of the lesion. Initially there is no clear intermediate zone between the frozen and the normal tissues, but within 30 min there is a distinct band some 10-30 cells broad separating the injured from the normal tissue (fig. 5). This corresponds exactly to the periphery of the damaged zone. The ultimate fate of this intermediate area is uncertain. It becomes progressively less distinct but simultaneously and at an early
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Fig. 5. Light-microscopic appearance showing the typical junction zone at the periphery of the cryolesion. a 24 h after freeze. x 10. b Six days after freeze. x 10.
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stage there is peripheral fibroblastic activity. Thereafter it appears to pass through a phase of organisation until it finally forms a distinct fibrous capsule to the lesion. Within the injured tissue there is evidence of cellular fragmentation and a marked increase of the intercellular spaces, much of this space being filled with extravasated erythrocytes. At this stage the cells are shrunken with progressive pyknosis and the intracellular details obscured. Thereafter the changes do not differ greatly from those associated with an ischaemic infarct. The dilatation and sludging progresses to thrombus formation in vessels and ultimately disintegration of the vessel wall. There is increasing margination and emigration of cells through the wall with a rapidly increasing cellular infiltration composed mainly of polymorphs, and with lymphocytes and plasma cells confined primarily to the margin of the lesion. Throughout this process the tissues adjacent to the frozen area show little morphological change and by the time of organization the surrounding structures are indistinguishable from normal. Tissue interphases are no barrier to the development of the freezing boundary and the changes that have been described occur in all tissues. Smaller blood vessels are obstructed by thrombus formation at an early stage. Large blood vessels behave in an interesting manner in that although there is the anticipated cell death in all layers, the integrity and strength of the vessel wall is unaffected largely as a result of the elastic tissue component. Blood flow returns on thawing in all but the smaller vessels and there is no evidence of late aneurysm formation. Similarly bone may be incorporated into an iceball and although the cellular element is destroyed it retains its structural integrity and strength and is ultimately recolonised with its normal cellular components. The appearances on electron microscopy are as in the light microscopy, somewhat nonspecific. The first visible changes appear at 15 min after the freeze with early crenation of the nuclei and mitochondrial swelling (fig. 6). At first the only cytoplasmic change is an occasional vacuolation. Throughout the 1st h there is dilatation of the endoplasmic reticulin with loss or fragmentation of the mitochondrial cristae and the appearance of grey areas and some dark bodies within the cytoplasm. The nuclear membrane remains intact up to 4 h, but by 6 h nuclei are barely distinguishable and by 12 h all cells appear dead (fig. 7). Although the ultimate pattern is of total and uniform cell death, electron microscopy does demonstrate that individual cells are not necessarily affected to the same extent or at the same rate as their immediate neighbours. The changes which follow cryosurgical injury to peripheral nerves
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Fig. 6. Electron-microscopic appearance 15 min after freeze showing early changes of nuclear crenation and mitochondrial swelling.
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Fig. 7. Electron-microscopic appearance 6 h after freeze showing gross nuclear fragmentation.
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are quite characteristic [5]. Cellular damage appears to be complete after 24 h and involves all components of the nerves. The sheath and axon are devitalised and there follows Wallerian and retrograde degeneration. The connective tissue of the nerve sheath, however, retains its integrity and remains as a continuous collagenous tube without evidence of inflammatory reaction. Provided the ganglion cell is undamaged revitalisation begins about 12 days after the injury and normal nerve architecture and function is complete within 30 days.
The ability to destroy all tissue regardless of its type means that freezing is particularly indicated in the treatment of tumours but its facility to be applied to any part of the body to which the probe can be introduced infers that it can destroy circumscribed volumes of tissue in otherwise inaccessible situations. Furthermore, by its accuracy of control it may be used to destroy predetermined volumes of tissue regardless of the dimensions. The constraints to its use at this stage in its development are restricted to the practical problems of identifying with accuracy the extent of the destruction, especially in malignant disease and in inaccessible sites. However, on the understanding that the limits of the cryolesion are at —15 0C and that this is from 1 to 2 mm from the edge of the visible or palpable iceball it is possible to assess either by sight, by touch or by the use of implanted thermocouples the likely extent of the zone of destruction. Thermocouples are usually designed in the form of a needle with a single temperature sensitive copper-constantan element at its end. Although efficient in determining the temperature at a single point, difficulty may be experienced in siting the tip and thereby in identifying the point. Alternatively a multiple thermocouple of the Benn-Merry type can be used. This carries multiple elements along its length and detects temperature changes at identifiable points during the iceball growth [4]. Since in some situations overfreezing is as undesirable as underfreezing the technique using thermocouples is either to calculate the required size of iceball before operation and to stop freezing at the predetermined point or to identify the temperature changes in the tissue outside the iceball. The latter technique depends on the principle that a temperature gradient develops well in advance of the expanding ice-water boundary [8].
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Clinical Application
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b Fig.8. a Locally extensive carcinoma of the breast. b The entire tumour mass is encompassed by repeated and multiple applications.
Freezing is commonly used for primary skin tumours or metastatic deposits in or immediately beneath and involving the skin, but it can also be used to treat any surface tumour such as within the nasopharynx, the alimentary tract, the bladder or the peritoneal cavity. Α small skin tumour up to 4-5 cm in diameter can be completely obliterated and the results in terms of cosmetic appearance are unequalled by other methods. Unfortunately, when the probe is applied to the surface the resultant iceball will
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Surface Tumours
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take the form of a hemisphere while the malignant tumour with its deep extension is more comparable in shape to the iceberg. For this reason it is usually necessary to freeze a large area of skin to encompass the entire growth. As an example cryosurgery is ideally applicable to recurrent chest wall and axillary breast cancer. Relatively large tumour masses can be destroyed especially if a technique of repetitive freeze is used the resultant ulcer epithelialising rapidly (fig. 8, 9). In practice it is preferable to encompass the entire tumour mass by multiple applications on the first occasion even though this does infer an overfreeze and destruction of
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Fig. 9. Basal cell carcinoma of the cheek. a Before freezing. b Six weeks after a single freeze.
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normal surrounding tissue. The alternative technique is to destroy the greater part of the tumour on the first application, further freezes being required for residual tumour. In either circumstance it is important that there should be the widest and closest possible contact between the probe and the target tissue. The property of cryoadhesion ensures that provided the surfaces are moist there will be a firm bond, but it must be emphasised that this feature of freezing occurs maximally if the probe is applied when warm and cooled in that position. If it is cooled to —80 0C or below before being applied the adhesion is weak. In surface tumours and elsewhere the contact can be increased by inserting the probe tip directly into the tumour mass. Although in theory this trauma is capable of releasing cancer cells into the circulation this is probably irrelevant in most circumstances. It has the additional advantage of allowing the iceball to be sited in an optimal position within the tumour mass. Tumours which lie below healthy skin or other surface epithelium can be frozen by applying the probe directly to
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Fig.10. Chest wall recurrence of carcinoma of the breast. Cryoprobe applied directly to the tumour mass through a small skin incision.
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the overlying skin. The frozen skin will die with the tumour but the resultant ulcer heals rapidly and completely. The alternative technique which is probably preferable is to incise the skin and to apply the probe directly to the tumour. The undamaged skin flaps heal satisfactorily even though they lie on dead tumour tissue (fig. 10). Other surface tumours such as basal cell carcinoma, squamous carcinoma and malignant melanoma are equally suitable for cryocoagulation though in primary tumours of this nature it is essential that adequate destruction be obtained at the first sitting. Where there is no histological confirmation of the diagnosis a biopsy can be taken from the frozen tissue without bleeding, or fear of dissemination. The piece of tissue removed is managed while still solid as a typical frozen section. Anaesthesia is frequently unnecessary in the treatment of surface tumours but there are occasions in which the patient experiences a frostbite type of discomfort and local anaesthesia with mild sedation is usually adequate analgesic.
Cryosurgery has many advantages in the management of simple lesions of the oral cavity. Granulomata, papillomata, fibrous epulides and hyperplastic lesions are obvious examples especially where orthodox excision has recognised disadvantages. Surface changes, such as leukoplakia, can be totally eradicated and if a purpose-designed probe tip with a relatively large surface area is used the depth of destruction need not be excessive. Tonsillectomy has been carried out with great success using a cryoprobe. Vora LEDEN [19] comments on the special value of this technique when the surgical problem is complicated by a blood dyscrasia such as haemophilia, Von Willebrand's disease and thrombocytopaenia [10]. The morbidity is minimal in all cases and there are no specific contraindications. Vascular lesions such as oral or facial angioma, haemangioma and lymphangioma form an ideal group for control by cryosurgery [17]. The small lesions are usually manageable by a single freeze but extensive or deep involvement probably requires several applications. Because of the vascular nature of the tumour and the heat sink effect of the major feeding vessels this is one of the occasions in which the more powerful liquid nitrogen cryoprobe must be used. Excellent cosmetic results may be obtained though on occasions there may be slight fibrosis and in the typical port wine stain the overlying skin seldom returns to normal.
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Oral and Maxillofacial Regions
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In the management of malignant tumours of the oropharynx Posωτnο [16] has shown that cryosurgery has advantages over alternative treatments. With care the tumour can be totally eradicated without scarring or loss of the vermillion border on the lip and the capacity of this method for controlling the dissemination of tumour cells by immobilising them within the iceball is an obvious advantage. In these circumstances, as in surface skin tumours, overfreezing is essential. Α rapid freeze to temperatures below —80 0C is almost certainly required and it is an indication for a liquid nitrogen probe rather than the less powerful Joule-Thomson equipment. It is a further indication for repetitive freeze rather than a single application. Malignant tumours invading neighbouring structures can be frozen without hazard, for example, to the underlying bony structures, there being no likelihood of sequestrum formation or of painful persistent ulceration. Finally the larger primary or recurrent oral and nasopharyngeal cancers are ideally treated by cryosurgery. In these circumstances it is unlikely that a complete control can be obtained at one sitting, but the resultant benefits in relief of pain, control of surface discharge and haemorrhage are most gratifying and there is no contraindication to repeated applications. In extensive tumours the possibility of freezing uninvolved structures even within the cranial cavity is disregarded. Cryosurgery has many advantages in the management of malignant lesions of the oropharynx and nasopharynx. The probe can usually be applied even in the most inaccessible sites. It can be used repeatedly even in the poor risk patient and there is much less disability in the postoperative care period. The structure and function of the normal tissues, especially the bony facial skeleton, is retained. Complications are rare. Finally, it may be used in the presence of heavy surface infection and even in radioresistent tumours. On occasions the regression of tumour tissue is striking, but even in palliative circumstances the relief of symptoms can be dramatic. Obviously the tumours that respond most favourably to freezing are the locally malignant varieties, such as the adenoid cystic carcinoma and the basal cell carcinoma, but the only contraindication is evidence of rapidly advancing, widespread disease in which the patient may not survive long enough to obtain the maximum benefit from the local treatment. It must therefore be remembered that a full epithelial cover may be delayed for up to 6 weeks after the freeze.
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Cryosurgical equipment was first designed for use in neurosurgery and it was obviously in this field that most of the pioneer work on cryogenic techniques was undertaken. Its particular properties of accuracy of control, haemostasis and the creation of a hard iceball in friable tissue made it eminently suitable for brain surgery. In soft tumours the probe is applied at craniotomy and the iceball is allowed to grow until it encompasses the tumour growth, which is then separated by blunt dissection and without difficulty from the normal surrounding brain tissue. Alternatively, since it is known that the frozen tissue will die the tumour can be allowed to thaw and left in situ. Initially there is considerable local oedema but thereafter the degenerative changes progress without affecting the surrounding structures. The possibility of an initial reversible lesion in which the probe is first applied at a temperature cold enough to paralyse the affected cells but well above their freezing point is an additional attraction. In parkínsonísm and choreoathetosis, the specific areas within the brain responsible for these movements can be identified by inserting a small 2-mm probe under local anaesthesia. When sited in roughly the correct area the temperature is gradually lowered and the brain tissue cooled. The subsequent effects on the patient's symptoms indicates whether the probe is correctly situated. If the tremor is insufficiently corrected the probe is withdrawn and repositioned without permanent injury. When the position has been confirmed the surgeon reduces the temperature to a lethal degree and destroys with accuracy the relevant small groups of cells. A similar reversible technique can be used to identify and to destroy pain-carrying fibres in the spinothalamic tract of the spinal cord in patients with painful irremovable malignant disease within the pelvis, or lower extremity. In both the intracerebral and spinal cord situations a stereotactíc technique is used in preference to an open operation. Destruction of the pituitary by cryohypophysectomy is indicated in patients with primary tumours of the pituitary such as the acidophiladenoma, in patients with breast cancer and in certain cases of diabetes mellitus in which it is known that pituitary ablation may result in a regression of the associated retínopathy. In this technique a trocar and cannula are inserted through the nasopharynx and enter the pituitary fossa through the sphenoid, the trocar is withdrawn and a small probe passed down the cannula. The position of the cannula is usually controlled by a stereotactic harness, though a free-hand technique with continuous radio-
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logical monitoring is equally effective. The pituitary and its stalk can be destroyed totally without difficulty but care must be taken to avoid damage to neighbouring structures, especially the optic chiasma. In these circumstances some means of predicting the size of the iceball is essential since the lesion cannot be assessed visibly or by palpation. The technique of cryohypophysectomy is further influenced by the presence of considerable heat sinks in the form of internal carotid arteries, and allowance has to be made for this factor in the prediction. For this reason and the fact that the 2-mm probe is relatively low-powered it is usual for two small symmetrical iceballs to be created on either side of the pituitary fossa rather than one single all-encompassing lesion. There are few complications following cryohypophysectomy. Rhinorrhoea may occur for a few days but it is less significant that after pituitary implantation, meningitis has not been reported, though it is customary to give prophylactic antibiotics. Diabetes insipidus may occur. In general the technique is less efficient than an open operation but it is safe, effective and is ideally suited to high-risk patients.
The usual cryoprobe is designed with a non-insulated tip for terminal freezing but special purpose probes have been designed for specific operative procedures. One of these has a curved end similar in shape to a coudé catheter with a pre-terminal non-insulated segment. This instrument can be introduced into the prostatic urethra and by creating a lemonshaped iceball over the non-insulated segment it can freeze an equivalent shape and volume of prostatic tissue. Cryoprostatectomy is more comparable to the transurethral resection than to an open operation in that it clears a passage through the prostatic urethra rather than ablating the entire adenomatous tissue. The extent of the iceball can be determined either by thermocouples implanted through the capsule of the prostate or by the more crude but equally effective methods of palpating the iceball with a finger in the rectum. The frozen segment of the gland undergoes the usual ischaemic necrosis and the slough is either passed per urethra or gradually disappears in about 3 weeks. There is no significant haemorrhage during or following the procedure but an indwelling catheter must be left in position for up to 10 days. Complications do occur, including post-operative urinary infection, epididymo orchitis, penile oedema, and osteitis pubis. In general,
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however, the results of treatment are satisfactory with early painless micturition, no residual urine, and an adequate return to normal control [11]. This technique is obviously no better than the standard operations for the fit patient with a simple prostatic hyperplasia, but it is especially indicated for prostatic carcinoma and for patients suffering from an associated disease, such as the respiratory cripple unfit for general anaesthesia [17]. It is also ideally suited for patients on anticoagulant treatment or suffering from a bleeding disease such as haemophilia. Although there may be residual adenomatous tissue which could recur the extent of the trauma is such that repeated cryoprostatectomy is a quite acceptable form of management in high-risk patients. Ophthalmology The property of freezing that is most utilised in ophtalmology is that of cryoadhesion, namely, the fact that any metal object, when frozen, will adhere firmly and permanently to all damp living tissues. The removal of the opaque lens from the eye in a cataract operation is greatly facilitated by placing a small relatively low-powered cryoprobe in contact with the periphery of the lens. A bond is formed between the probe and the lens which is strong enough to allow a gentle but controlled manipulation and extraction. In other ophthalmological disease local freezing may also be of value, for example to produce a minute point of tissue coagulation through the sclera as part of the fixation of a detached retina or to control inflammatory disease.
The indications for cryosurgery in gynaecology are not dissimilar from the indications elsewhere, namely, to destroy localised benign disease and to control invasive tumours, especially when alternative methods are not available or practicable. There are two particular fields, however, in which the technique has special merit. In disease of the cervix, such as the small in-situ carcinoma and cervical erosions a specially shaped cryoprobe can be inserted into the external os. The resultant iceball destroys the local disease but the absence of local scarring prevents injury or stensis of the cervical canal. Epithelial cover occurs rapidly and is complete even in the
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presence of extensive and deep erosions with gross superlicial infection. Freezing may also be used to remove labial and perineal venereal warts and if used correctly is highly successful. It is an interesting application of the technique, however, since viruses are peculiarly resistant to rapid freezing and low temperatures, and unlike other disease relatively mild cooling is more effective than the usual rapid freeze. Alternatively, repeated exposures can be successful in resistant cases. Cryohaemorroidectomy A somewhat specific use of cryosurgery is in the management of haemorrhoids. In this situation the three primary pile masses are individually frozen to create three separate iceballs. Each haemorrhoid is in turn withdrawn through the anal canal and the cryoprobe is laid along its surface. The tissue undergoes the usual aseptic necrosis with separation of the slough and early epithelial cover. The complete process may take up to 6 weeks and is accompanied by considerable local discharge but there is no discomfort, no bleeding and the final result is cosmetically and functionally most satisfactory. The advantage of this technique is that it requires minimal hospitalisation, it can be undertaken with minimal anaesthesia and is eminently suitable as outpatient treatment or for the high-risk patient. Other Indications Cryosurgery has been used in many other circumstances varying from the treatment of verrucae to the obliteration in situ of hepatic metastases or as an adjuvant to a partial hepatectomy and in the treatment of localised tumours within the abdominal cavity and in the lungs. In each of these situations the destructive capabilities ensure that the frozen tissue is destroyed but its use is only of significance if the tumour can be totally encompassed by the iceball.
The cryoprobe is regarded as a sophisticated instrument of destruction and has an undoubted value in its own particular field. It is likely that in
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the future its use will be widened to include new sites within the body and the treatment of a wider range of diseases. Improved technique may result in larger volumes of tissue destruction and a greater understanding of the nature of the destructive agent will result in a finer control of this destruction and a greater ease of predictability in concealed sites. Recently it has been suggested that within a tumour destroyed by freezing there is a release of tissue proteins which acquire new antigenic properties or of pre-existing but unavailable antigens [15]. The result of this is the development of an immune response to the target tissue and probably related directly to the freezing injury. It is accepted that this release of antigenic substance occurs during the relatively slow thawing period rather than in the initial freeze and as such differs from the effects of other forms of tissue injury. The first report of this antigenic response was made by Asux et al. [1, 2], who identified specific autoantibodies in the male rabbit following cryocoagulatíon of the accessory gland of reproduction. These investigations paralleled a report in which metastatic deposits of prostatic carcinoma were seen to regress following repeated cryocoagulation of the prostatic primary. More recently antibody responses have been demonstrated after treatment of rectal carcinoma, malignant melanoma and basal cell carcinoma. These isolated reports are suggestive of an acquired response against the injured tissue but they are insufficient to allow us to assume that there is now firm evidence of a clinically significant immune response against malignant tumours. Ø the other hand should this phenomena be substantiated its potential application to cancer therapy would be a most exciting prospect.
1 ABLIN, R. J. ; SολνΕs, W. Α., and GoinoR, M. J. : Clinical and experimental considerations of the immunological response to prostatic and other accessory glands of reproduction. Urol. int. 25: 511 (1970). 2 ABLIN, R. J. ; Somas, W. Α., and GoinoR, M. J. : Elution of in vivo bound antiprostatic epithelial antibodies following multiple cryotherapy of carcinoma of prostate. Urology 11: 276 (1973). 3 ARNorr, J.B.: On the treatment of cancer by the regulated application of an anaesthetic temperature (Churchill, London 1851). 4 Bau, D.N. and MERRY, J.J.: Α multisensor cryogenic temperature probe. Proc. int. cryogen. Eng. Cont. 4: 375 (1972). 5 CARTER, D.C. ; LEE, P. W. R. ; Giri, W., and Joηνsrοκ, R. J.: The effects of cryosurgery on peripheral nerve function. AØ. R. Coll. Surg. 17: 25 (1972).
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References
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Prof. J. FRASØ, Professor of Surgery, Faculty of Medicine, Surgical Division, The University of Southampton, Fanshawe Street, Southampton S09 4ΡΕ (England)
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6 COOPER, I. S. and LEE, A. St. J. : Cryostatic coagulation; a system for producing a limited controlled region of cooling or freezing of biological tissues. J. nerv. ment. Dis. 133: 259 (1961). 7 FARκπκτ, J. : Some mechanisms of freezing injury. Proc. Int. Congr. Cryosurg, p.23 (1972). 8 Gn L, W. ; DA COSTA, J., and FRASER, J. : The control and predictability of a cryolesion. Cryobiology 6: 347 (1970). 9 GILL, W. ; FRASER, J., and CARTER, D. C. : Repeated freeze/thaw cycles in cryosurgery. Nature, Lond. 219: 410 (1968). 10 GILL, W. ; FRASER, J. D. ; LoNG, W., and LEE, P. W. R.: Cryosurgery for neoplasia. Br. J. Surg. 57: 494 (1970). 11 GoiioR, Μ. J. ; SoAias, W.A., and SmiLlAi, S.: Cryosurgical treatment of the prostate. Investie Urol. 3: 372 (1966). 12 LEmo, S.P. ; FARRπκΤ, J. ; ΜλzuR, P.; Ηλννλ, M.G., and SMITH, L.H.: Effects of freezing marrow stem cell suspension. Cryobiology 6: 315 (1970). 13 MARSHALL, A.: Cryogenic surgery of the prostate. Proc. R. Soc. Med. 61: 1139 (1968). 14 MERYMAN, H.T.: Cryobiology, pp.2-91 (Academic Press, New York 1966). 15 MYERS, R. S. ; Hλµµονn, W. G., and ΚΕΤCHΑM, A. : Tumour specific transplantation immunity after cryosurgery. J. Surg. Inc. 1: 241 (1969). 16 PoswxLLo, D. : Cryosurgery and electrosurgery compared in the treatment of experimentally induced oral carcinoma. Br. dent. J. 131: 347 (1971). 17 PoswτLLO, D. : Comparative study in the effects of electrosurgery and cryosurgery in the management of benign oral lesions. Br. J. oral Surg. 9: 1 (1971). 18 SMιrκ, J. J. and FRASER, J. An estimation of tissue damage and thermal history in the cryolesion. Cryobiology 11: 139 (1974). 19 LEDEN, Η. voi: Current trends in cryosurgery of the head and neck Cryosurgery 1: 160 (1968). 20 WHAArAKER, D. K.: Ultrastructural changes in oral epithelium following cryogenic surgery. J. dent. Res. 48: 118 (1969).
