Cryosurgery in aggressive, benign, and low-grade malignant bone tumours

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1 Cryosurgery in aggressive, benign, and low-grade malignant bone tumours René Veth, Bart Schreuder, Herman van Beem, Maciej Pruszczynski, Jacky de Rooy Cryosurgery is a method of treatment for various tumours that induces tissue necrosis with ablative intent. It is used in benign, aggressive, and low-grade malignant bone tumours such as chondrosarcoma grade 1. We describe the history of the technique and the issues associated with cryobiology, as well as the indications, technique, complications, and results of cryosurgery. At the University Medical Centre Nijmegen, Netherlands, 302 tumours have been treated by use of cryosurgery with at least 2 years follow-up % of patients were cured the response depended on tumour type. Comparison of functional results with data from studies shows that these results concur with other studies on cryosurgery, and are at least equal to results of marginal excision and mostly better than those of wide excisions of grade 1 chondrosarcomas. Thus from an oncological point of view, cryosurgery combined with intralesional excision is equal to marginal excision. Cryosurgery uses low temperature to induce tissue necrosis with the intent of ablation by four processes: freezing, holding of freeze, thawing, and repetition of these cycles. A minor cryogenic injury leads only to an inflammatory response, whereas a major cryogenic injury causes tissue destruction. James Arnott 1 was the first to use cryosurgery for treatment of skin lesions, breast cancer, and cervical cancer. In the past, solid carbon dioxide, cold-air blast, and liquid nitrogen were used as cryogenic agents in the treatment of benign and malignant tumours. 2 Cage 3 showed in 1966 that liquid nitrogen induced bone necrosis in malignant oral-cavity lesions of soft tissues, followed by new bone formation and complete recovery. Moreover, Marcove and Miller 4 were pioneers of orthopaedic cryosurgery. Liquid nitrogen seemed to obtain good tumour control with minimum postoperative defecits in bone and function. In the Netherlands, Oeseburg 5 first applied cryosurgery for treatment tumours, which initially lead to complications such as skin necrosis, infection, fracture, and neuropathy and therefore hindered acceptance of this technique. However, since the early 1970s, prevention of complications has been possible and confidence in cryosurgery for musculoskeletal disorders has grown. Cryosurgery commonly cures aggressive, benign, and low-grade malignant bone tumours, and can palliate radioresistant bone metastases of various origins. In this context, the oncological result of cryosurgery is equal to that of marginal or wide excision (figure 1), 6 and is also less expensive because, unlike marginal or wide excision, prosthetic implants are not needed for reconstruction. membranes allow for permeation of water, but less readily for passage of solutes. When tissue is cooled slowly, it first enters a super-cooled phase without ice formation. Temperatures of 10ºC to 15ºC initiate Tumour Surgical margin Cryosurgical margin Lancet Oncol 2005; 6: Departments of Orthopaedics (Prof R Veth MD, B Schreuder MD); Anaesthesia (H van Beem MD); Pathology (M Pruszczynski, MD); and Radiology (J de Rooy, MD), University Medical Centre Nijmegen, Netherlands Correspondence to: Prof René Veth, Department of Orthopaedics 800, University Medical Centre Nijmegen, Postbox 9101, 6500 HB Nijmegen, Netherlands R.Veth@orthop.umcn.nl Cryobiology and cryotreatment Cryobiology is the study of physical effects in living tissue that are induced by changes in temperature. To destroy tissue, the physical characteristics of the main component of living organisms ie, water are used. However, the freezing of tissue is complicated because its solvent (water) is divided by cell membranes into extracellular and intracellular compartments. Cell Bone graft Figure 1: Nijmegen cryosurgical procedure White regions are tumours, peach is the reactive zone around the tumour, and violet is the postexcision surface treated with nitrogen. Use of this technique can ablate tumours, leading to a 1 8-cm margin (equal to marginal excision). Reproduced with permission from ref 6. Vol 6 January,

2 extracellular ice formation; the intracellular compartment remains unfrozen because it contains substances of high and low molecular weight. Extracellular freezing of water causes the concentration of solutes in the compartment to rise, leading to transport of water from the intracellular to the extracellular compartment as a result of osmotic pressure. This loss of water causes the cell to shrink and is accompanied by high concentrations of solutes (especially salts), which further prevents the formation of ice in the intracellular compartment and could cause injury to cells. 7 This process is thought to be especially important during slow cooling. Very rapid cooling induces intracellular ice formation because there is too little time for water to leave the cell to maintain osmotic equilibrium across the cell membrane. 7,8 Frozen tissue is subjected to shearing forces and propagation of ice, which causes mechanical damage to the membrane and causes dysfunction of cell organelles Slow thawing is accompanied by recrystallisation so the damaging effect of intracellular ice crystals can thus be exploited a second time. 7 The longer the thawing, the larger the ice crystals will grow and the greater the mechanical damage to the cells. However, if tissues have been cooled slowly, causing shrinkage and intracellular dehydration, rapid thawing can also damage cells because of exposure to high concentrations of electrolytes. 12 After thawing there is typically a brief period of vasodilation. Furthermore, the endothelium of blood vessels is especially sensitive to freezing and thawing and leads to increased permeability of vascular walls, interstitial oedema, slowed circulation, and platelet aggregation. 13 Ischaemia in cryosurgically treated tissues deprives all cells of any possibility of survival and results in uniform necrosis of tissue, except at the periphery of the lesion. In bone, microangiography has shown total avascularity of the cortex after cryosurgery. 14 The exact temperature thought to be lethal to cells has decreased during the past 50 years: in 1946, between 10ºC and 20ºC was thought to be sufficient, 15 but soon after 30ºC was the lethal threshold. 16 For treatment of cancer cells, 50ºC to 70ºC in vivo is advised at present. 17,18 We have shown 19 that three cycles of intramedullary freezing with a closed liquid-nitrogen cryoprobe induced necrosis in healthy bones of rabbits until 10ºC. Studies 20 have shown that destruction of long-term frozen tissue is more intense while holding the freeze than when the freeze is not held. Several cycles of freeze thaw are needed because living tissue becomes resistant to thermal injury. After the first cycle, thermal conductivity in the tissue is increased, and the specific heat capacity and vascularity of the tissue are decreased. These events precondition the tissue to make the next cycles more effective by faster cooling and slower thawing. 17 Figure 2: Low-grade chondrosarcoma Calcifications and entrapment of eroded bone fragments by cartilaginous tumour. Haematoxylin and eosin stain (magnification 100). Histological changes of frozen bone after cryosurgery are seen only after several days. Osteocytes disappear slowly, and within 7 days the frozen bone has no living cells. After a few days, osteogenesis at the border of the devitalised segment is seen, which replaces dead bone by a process of creeping substitution. During this period, the bone is weakened and fractures can occur easily We contend that bone responds to freezing in a unique way whereby cellular elements but not the calcified matrix are destroyed because the matrix, unlike soft tissues, maintains the structural integrity. Suitablility of tumours for cryosurgery Several benign and malignant bone tumours can be treated by cryosurgery. 24,25 Here, we discuss low-grade malignant and benign tumours that have metastatic potential or that warrant further discussion (eg, symptomatic enchondroma, borderline chondrosarcoma, lowgrade chondrosarcoma, chondroblastoma, chordoma, and giant-cell tumour ). Enchondroma is a benign medullary cartilageproducing lesion that accounts for about 13% of all benign bone tumours and occurs mostly in the second to fourth decades of life. 50% of enchondromas arise in small bones of the hands and feet, the other half in the humerus and femur. 26 In long bones they are mostly asymptomatic, whereas in small bones they are expansive with attenuation of the cortex that leads to pathological fractures and pain; invasion of soft tissue is not seen. 26 Enchondroma can be solitary or multiple, resulting in enchondromatosis. Chondrosarcomas are the third most common primary malignant bone tumour after myeloma and osteosarcoma, and are a heterogeneous group with several variants and grades. Most patients are men older than 50 years, 27 and typical localisations are to the pelvis, femur, humerus, and ribs. The typical presentation is swelling and pain, especially during rest. 28 Chondrosarcomas can show differentiation of pure 26 Vol 6 January, 2005

3 hyaline cartilage, but myxoid changes, calcifications, and ossification are also common. Microscopically, conventional chondrosarcomas are hypercellular, show atypical nuclei, penetrative growth in medullary bone, entrapment of bony trabeculae by tumour, and invade through the cortex into soft tissue (figure 2). Necrosis and mitotic activity are found in high-grade tumours. Grading is useful in prediction of behaviour and prognosis, 29 for example, low-grade tumours are locally aggressive. A third of high-grade chondrosarcomas metastasise early, especially to the lungs, 5-year survival is 89% for patients with histological grade 1 chondrosarcoma; 5-year survival for patients with histological grade 2 and 3 tumours is 53%. 28,30 Furthermore, DNA ploidy is an important prognostic factor: 31 25% of patients with grade 1 chondrosarcoma have an appearance identical to enchondroma on microscopy, 32 and their distinction is one of the most difficult problems in bone-tumour pathology (differential diagnosis often relies only on the clinical picture and radiological findings). Thus, the pathologist may be forced to make an unsatisfactory diagnosis of borderline chondrosarcoma. About 10% of chondosarcomas dedifferentiate, 28 and we think that only borderline chondrosarcoma and histological grade 1 chondrosarcoma are suitable for treatment with cryosurgery. Chondroblastoma is a benign chondroid neoplasm usually found in the epiphysis of long bones in patients with immature skeleton. It accounts for less than 1% of all bone tumours, 33 and consists of immature chondroblasts, commonly with pericellular, chickenwire, calcifications. Extreme cellularity and admixture of giant cells are sometimes confused with giant-cell tumours. Some, mostly pelvic, tumours show local aggressiveness and invasion of soft tissues. Recurrence after surgery without adjuvant treatment occurs in 5 38% of patients. 34 Metastases to the lungs can occur, mostly after surgical manipulation of the primary tumour. Chordoma is a low-to-intermediate grade malignant neoplasm that arises from notochord remnants and accounts for 1 4% of all primary malignant disorders in bone. Patients are generally older than 30 years, and tumours are most often localised to the axial spine (usually in sacral or spheno-occipital area). 32 Chordomas generally destroy bone and extend to surrounding soft tissues, and are divided into conventional, chondroid (which are associated with longer survival), and dedifferentiated (associated with poor outlook). 35 Microscopically, they have myxoid stroma, cellular variability, and characteristic multivacuolated cells. Metastases occur usually in advanced cases and mostly to the lungs, soft tissues, bone, or lymph nodes. Giant-cell tumours constitute 4 5% of all primary bone tumours and have a higher incidence in females; incidence peaks in year-olds. Common localisations are epiphyses of long bones, but other sites, Figure 3: Giant-cell tumour Mixture of mononuclear spindle cells and multinuclear giants cells, with eroded cortical bone in upper left corner. Haematoxylin and eosin stain (magnification 200). even the skull, can be involved. 36 Multicentricity has also been reported, and many patients have a pathological fracture On microscopy, neoplastic mononuclear stromal cells and reactive giant cells that resemble osteoclasts with histiocytic markers can be seen, and immunoreactivity and focal calcifications are also visible (figure 3). Mitotic activity is invariably present, but pronounced atypia is seen only in malignant variants: true malignant transformation is rare and commonly follows radiotherapy. 37 Surgical stage has been associated with prognosis, but histological grading does not have high prognostic importance, except for tumours that are evidently malignant. 36 Non-random chromosomal abnormalities (eg, fusion of telomeres) have been found in clinically more aggressive tumours. DNA ploidy, proliferation index, and vascular density have not been proven to show prognostic importance, but overexpression of P53 might mean higher potential for recurrence and metastases. 38,39 Giant-cell tumour of bone should be regarded as a low-grade malignant disorder because of potential metastasis and recurrence irrespective of histological appearance. In our opinion, only benign tumours of this type are suitable for cryosurgery. Indications for cryosurgery Benign and malignant bone tumours are staged according to their biological, clinical, and histological characteristics, and the treatment needed for local control of the tumour has been defined for every stage. 40 (latent benign bone tumours are inactive and do not need treatment). Active and aggressive, as well as lowgrade malignant, bone tumours can be treated with extralesional (either marginal or wide) excision. For tumours in expandable bones, such as the ribs, excision is the treatment of choice. However, because most aggressive, benign, and low-grade malignant bone tumours tend to occur in the metaphysis and epiphysis Vol 6 January,

4 Figure 4: Treatment of giant-cell tumour (A) Pathological fracture at admission in a 18-year-old girl. (B) Tumour after cryosurgery, osteosynthesis, and allografting. (C) 4 years after surgery and completely disease free. See next issue of The Lancet Oncology (February, 2005) for a Review on surgical options for children with osteosarcoma of long bones, marginal or wide excision would cause segmental loss and would compromise normal growth in children, and cause loss of the articular surface. Furthermore, excision at these sites would need reconstruction with a prosthesis or segmental allograft and the technique of intralesional excision curettage combined with a powerful local adjuvant is advocated in these types of tumours. After curettage, minor reconstruction within the borders of healthy structures will be sufficient. Adjuvant therapy can consist of systemic chemotherapy, radiotherapy, physical adjuvants such as locally applied phenol or polymethylmethacrylate, and cryosurgery. Chemotherapy and radiotherapy target mitotically active cells and their effect on benign bone tumours is thus limited and inappropriate because of their side-effects and risk of secondary sarcoma after irradiation. Phenol is a non-selective cytotoxic agent and, when applied directly to the surface of curetted bone tumours, kills residual tumour and healthy cells. However, local recurrence of % has been reported, probably because of superficial action and the impossibility of penetrating the peripheral surgical margin. 41 The rationale for use of polymethylmethacrylate cement as adjuvant treatment is based on its heating and potentially stabilising effect. Studies have shown that a temperature of at least 50ºC is needed for cytotoxic effect. The maximum peripheral extent of a thermal lesion induced by polymethylmethacrylate cement varies from 2 5 mm in cancellous bone to only 0 5 mm in cortical bone, which is insufficient. 24 Cement in a post-tumour defect is a less effective biological method of reconstruction than is bone allograft, and the transient presence of a plate and screws for initial reconstruction means a complete biological reconstruction. Cryosurgery is a powerful adjuvant that enhances the local extent of treatment by at least 7 12 mm beyond the surgical margin and allows for adequate tumour kill. 24 Skeletal metastases are usually given radiotherapy. However, in patients with radioresistant disease or who have had surgery because of a (pending) pathological fracture, adjuvant local control can be achieved by cryosurgery. Treatment Standard orthopaedic methods are used to access the tumour for cryosurgery tumours (figure 1). Extremity tourniquets are not used because a healthy circulation decreases the risk of freezing near neurovascular bundles and skin. An oval window is made in the cortex to excise the tumour intralesionally (figure 1). To monitor the intralesional temperature and local extent of freezing, thermocouples are positioned in and around the lesion, one of which next to the neurovascular bundle to give information about corrective action needed to prevent inadvertent freezing. Three cycles of cryosurgery are routinely done by use of a machine that produces a liquid-nitrogen spray, which is directed into the lesion in every direction until the whole cavity becomes frozen to at least 50ºC; spontaneous thawing warms the tissue up to 20ºC. After three cycles of cryosurgery the entire wound and cavity is lavaged with sodium hyponitrate to prevent seeding of tumour cells. After curettage and cryosurgery, the defect is filled with autograft or allograft bone chips (figure 4). If the strength of weight-bearing bones is compromised by the tumour and by cryosurgery, prophylactic internal fixation is advised. Intramedullary enforcement should not be done because of risk of tumour-cell contamination of the entire intramedullary compartment. If needed, titanium-alloy osteosynthesis implants are used because they do not interfere with MRI at follow-up (figure 4). 42 Complications Intralesional excision of a tumour will create a cavity, and cryosurgery results in supplementary tissue necrosis. Furthermore, the defect is filled with a dead bone graft commonly with the addition of an osteosynthesis implant. These factors enhance the risk of infection; cryosurgery is associated with an incidence of infection as high as 4% Use of perioperative broad-spectrum antibiotics is needed to avoid infection. We have found an increased blood flow in the area of cryosurgery, which shows the need for adequate drainage after surgery Vol 6 January, 2005

5 Figure 5: Low-grade chondrosarcoma of the femur (A) Before treatment. (B) After cryosurgery, osteosynthesis, and allografting. (C) 4 months postoperatively after fracture by adequate trauma, plate still intact. (D) Advanced repair of fracture 10 months postoperatively, no local recurrence. Cryosurgery can be sporadically complicated by gas embolism. 46,47 In our series, 47 this event occurred only once, while using an open probe. The mechanism of nitrogen-gas embolism is unclear but could be the result of liquid nitrogen that expands rapidly into gaseous phase in a confined bony cavity, which increases the pressure and introduces intravascular gas bubbles. Furthermore, if during cryosurgery the cavity surface becomes extremely cold, additional sprayed liquid nitrogen cannot vaporise. Thus, bone marrow acquires properties comparable with those of a sponge that sucks and traps liquid nitrogen in small marrow spaces. During thawing, trapped liquid nitrogen boils and vaporises, causing extremely high pressures and, because the solubility of nitrogen in blood is very low, it causes a gas embolus at the right side of the heart Vol 6 January,

6 that obstructs circulation through the lung and can lead to complete circulatory collapse. Risk is increased when the tumour is located in a richly vascularised area such as the metaphysis of long bones. Cryosurgical technique should never block the entrance to the bony cavity and should use a large cortical window for entrance. The first sign of impeded pulmonary circulation is a sudden decrease of expired carbon dioxide. As well as routine systemic monitoring, analysis of end-tidal gas is done by mass spectroscopy, which measures inspired and end-tidal tensions of oxygen, carbon dioxide, nitrous oxide, and nitrogen as well as concentration of anaesthetic vapour. Moreover, use of real-time recording of gas analysis breath by breath enables detection of exhaled nitrogen. Bone can be weakened by the tumour, the surgical exposure and resection, and by cryosurgery, and early studies reported high incidence of postoperative fracture (5 30%, figure 5). Studies 23,48 of the effect of cryosurgery showed that strength decreased by 30% 8 weeks after surgery; recovery was only seen after at least 4 months. However, prophylactic osteosynthesis and the bearing of partial weight after surgery for 3 months will prevent this complication. Benign bone tumours tend to occur in patients of immature skeletal age and commonly develop in the metaphysis adjacent to the epiphysis. Damage of the epiphysis can occur by the tumour itself or by use of cryosurgery and may lead to growth arrest or disturbance. 24 To minimise the risk of damage, protection of an exposed epiphysis seems logical, but will jeopardise the effectiveness of cryosurgery and can cause local recurrence of the bone tumour, permanently damaging the epiphysis. Control of the cryosurgical procedure and of the extent of local freezing can be done by monitoring with thermocouples. Some bone tumours eg, giant-cell tumour and chondroblastoma arise almost exclusively close to major joints. Damage to the articular surface either by the tumour or by cryosurgery should be anticipated, 24,25,45,49 and our experience suggests that articular cartilage is also be damaged by cryosurgery to some extent. 50 Nerve palsy is a transient complication of cryosurgery. 51 Most neuropathies resolve in 6 weeks to 6 months. 52 Because they remain intact, regenerating nerve fibres will probably grow down nerve sheaths initiated by nerve-cell nuclei in the dorsal root ganglions. Radiology and cryosurgery Preoperative imaging Bone tumours that are suitable for cryosurgery need standard radiological assessment beforehand. High-resolution plain radiographs of the affected bone in at least two perpendicular planes are needed for determination of the primary location of the tumour, bone destruction, periosteal reaction, and soft-tissue expansion. 53,54 Further imaging methods are generally used to assess invasion of the medullary cavity to define the feasibility of cryosurgery. 55 At present, MRI is assumed to be the most accurate method for assessment of the anatomical extent of bone tumours. 56 Distant metastases can be reliably ruled out by pulmonary CT and by skeletal technetium- 99-methyl diphosphonate bone scintigraphy. The most commonly used MRI for localisation tumours are T1-weighted and T2-weighted sequences, with or without fat suppression. Use of intravenous gadolinium with or without use of fast dynamic MRI techniques remains controversial. 57,58 MRI does not increase the specificity of tumour characterisation, but can be helpful in assessment of tumour cellularity and vascularity before and after adjuvant chemotherapy or radiotherapy. Contrast-enhanced MRI is also useful for definition of the volume of necrotic tumour compared with active tumour in large lesions, which simplifies the planning of biopsy. 59 Justification of the selection of lesions to be treated with cryosurgery can be done only after histopathological confirmation of the initial radiological diagnosis. Guidance with MRI or CT (depending on availability) of closed, percutaneous biopsies has proven to be effective if done by a skilled radiologist. 60,61 In summary, to ensure correct final diagnosis, close cooperation with the orthopaedic surgeon, radiologist, and pathologist is of high importance and is part of a multidisciplinary approach to management tumours. Perioperative imaging Although the first clinical results have been published on cryosurgery for renal and liver tumours monitored by MRI, 17 to our knowledge there are no further data on MRI-guided orthopaedic cryosurgery. Postoperative imaging Imaging of complications after surgery can be done with conventional radiography. For benign bone tumours, regular follow-up with plain radiographs should be sufficient to detect local recurrence. By contrast, low-grade malignant diseases need further MRI at regular intervals of 3 6 months. However, problems with visualisation are sometimes encountered when prophylactic internal fixation with plate and screws is done to prevent postoperative fracture. Even titanium alloys cause metal artefacts on MRI and need adjustment of standard MRI protocol. 62 Ultrasonography complements imaging of nonvisualised soft tissues nearby. 63 Little is known about the imaging characteristics of cryosurgery-related changes in the surrounding bone. High signal intensity on T2- weighted and low signal intensity on T1-weighted MRI are consistent with bone-marrow oedema, which might represent underlying thermal osteonecrosis. 64 Although fast dynamic contrast-enhanced MRI can visualise 30 Vol 6 January, 2005

7 Tumour Treatment Patients Follow-up (years) Local recurrence NED or CDF Functional score Ref Giant-cell tumour Cryosurgery (mean) 1 of 25 (4%) 24 of 25 (96%) Excellent and good, 24, 24 of 25 (96%)* chondroblastoma, or aneurysmal bone cyst Aggressive or Cryosurgery (range) 1 of 9 (11%) 8 of 9 (89%) low-grade malignant bone tumours (Borderline) Cryosurgery (mean) 0 of 22 (0%) 22 of 22 (100%) 29 4 (mean) 42 chondrosarcoma Giant-cell tumour Cryosurgery (mean) 8 of 101 (8%) 102 of 102 Excellent and good, 45 (100%) 94 of 102 (92%)* Giant-cell tumour Cryosurgery (minimum) 7 of 15 (47%) 17 of 17 (100%) Giant-cell tumour Curettage (minimum) 6 of 20 (30%) 22 of 22 (100%) Giant-cell tumour En-bloc excision (minimum) 0 of 11 (0%, lung 11 of 11 (100%) metastases in one patient) Giant-cell tumour Curettage (minimum) 5 of 10 (50%) 10 of 10 (100%) Giant-cell tumour Local excision (minimum) 21 of 28 (75%) 28 of 28 (100%) Giant-cell tumour Intraoperative (median) 3 of 12 (25%) 12 of 12 (100%) No data 68 phenol application Giant-cell tumour Curettage and (median) 3 of 14 (21%) 13 of 14 (92%) No data 68 bonegraft Giant-cell tumour En-bloc resection (median) 2 of 14 (14%) 14 of 14 (100%) No data 68 and reconstruction Giant-cell tumour Cryosurgery (mean) 0 of 24 (0%) 0 of 24 (100%) Excellent and good, 69, 20 of 24 (83%)* chondroblastoma, schwannoma, metastatic carcinoma Giant-cell tumour Cryosurgery (minimum) 8 of 43 (19%) 43 of 43 (100%) 11 20, 4 of 43 (9%); Veth R, 21 25, 4 of 43 (9%); unpublished 26 30, 35 of 43 (81%) data Borderline or grade 1 Cryosurgery (minimum) 3 of 117 (3%) 117 of , 9 of 117 (8%); Veth R, chondroblastoma (100%) 21 25, 22 of 117 (19%); unpublished 26 30, 86 of 117 (74%) data Chondroblastoma Cryosurgery (minimum) 1 of 14 (7%) 15 of 15 (100%) 11 20, 1 of 15 (7%); Veth R, 21 25, 2 of 15 (13%); unpublished 6 30, 12 of 15 (80%) data NED=no evidence of disease. CDF=continuously disease free. *As assessed by Enneking. 65 As assessed by Musculoskeletal Tumour Society. 66 Table: Cryosurgery and other surgery for aggressive, benign, and low-grade malignant bone tumours biological activity, future radiological investigations on cryosurgical effects should focus on use of this technique for early detection of tumour remnants or recurrence within regions of necrosis. With availability of high-field MRI systems for routine clinical use, faster dynamic techniques with higher spatial resolution will improve image quality further. Results of treatment All results are presented and discussed according to the Enneking grading system, 40 the former Enneking assessment system, 65 and the functional assessment system of the Musculoskeletal Tumor Society, 66 which has a maximum score of 30 or 30%. It is accepted throughout the world that these systems are needed for comparison of functional results after surgery for musculoskeletal tumours. The table compares functional scores and rates of local recurrences in patients with agressive, benign, and low-grade malignant bone tumours who were treated by different methods of surgery for musculoskeletal tumours. 302 patients received cryosurgery at our institution up to January, 2003, for various bone and soft-tissue tumours. At follow-up (minimum 2 years), 298 patients had no evidence of disease or were continuously free of disease, five were alive with disease, and two patients died of disease. Of eight patients with giant-cell bone tumours who had cryosurgery, three needed further cryosurgical procedures and sometimes radiotherapy to arrive at no evidence of disease. All 102 patients with borderline chondrosarcoma arrived at no evidence of disease, Vol 6 January,

8 Search strategy and selection criteria Published data were identified by searches of MEDLINE, Pubmed and CancerLit, using the search terms cryosurgery, cryotherapy, chondrosarcoma, giant cell tumour of bone, and chondroblastoma. Relevant textbooks were also used. Only material published in English between 1966 and July, 2004, was used, with the exception of two articles, one from 1850 and one from Useful websites Figure 6: Preoperative MRI of giant-cell tumour in the sacrum (sagittal section) although some needed a second cryosurgical procedure. Transient nerve palsy was seen in five patients with giant-cell bone tumours, one with chondroblastoma, and in four with borderline chondrosarcoma. By comparison of several studies 45,50,67,68,70 on the results of treatment for giant-cell tumour, a local recurrence of 27 0% after curettage only, 25 0% after phenol application, 7 9% after cryosurgery, and of 0% after wide en-bloc excision was found. Malawer 45 also found six pathological fractures postoperatively, three cases of skin necrosis, and degenerative arthritis in two of 102 patients. In addition to the results in the table, Van Loon 71 showed that 16 patients with low-grade chondrosarcoma, none of whom had been treated by cryosurgery, had no evidence of disease, two were alive with disease, and one died of disease. Functional results were on average 63% of the maximum score of the Musculoskeletal Tumour Society much lower than those of patients treated cryosurgically. Cryosurgery has also shown good results in giant-cell tumour in the hand 72 and in the sacrum (figure 6). 73 These results seem to concord with the review by Bickels 74 that the risk of local recurrence is small in cryosurgically treated borderline and low-grade chondrosarcoma but that functional results are better compared with marginal or wide excisions. In giant-cell tumour, functional results after cryosurgery are better than, or at least similar to, excision; however cure is commonly obtained only after repeated cryosurgical procedures. Malawer 24 (table) reported on 25 patients treated by cryosurgery for giant-cell tumour, chondroblastoma, or aneurysmal bone cyst and found that results compared favourably with those obtained by en-bloc excision. Wittig 72 showed good results after surgery for giant-cell tumour of the hand and, in 2003, Kollender 73 presented results of cryosurgery in 14 patients with sacral benign, aggressive, or low-grade malignant bone tumours (figure 6). Two patients developed local recurrence and none had substantial neurological deficit at follow-up. Future prospects Since the mid 1960s development of intraoperative ultrasonography (especially in visceral tumours) and of new methods for monitoring the process of freezing and thawing has meant that cryosurgery has evolved from a medical tool with limited use to a reliable treatment for many tumours including those of the bone. 17 Our research has shown that use of homologous bone grafts for filling bony defect is questionable in the diaphyseal area, but perhaps not for the metaphyseal area. Bone cement might be an appealing alternative, but further research is warranted. Robinson and co-workers 75 showed that two instead of three freeze thaw cycles would be sufficient for tumour control. Furthermore, Baust and colleagues 76 identified apoptosis as a cryosurgery-related mechanism of cell death that enhanced ice-related cell damage and post-treatment coagulative necrosis and which could be a possible route to molecular optimisation of cryosurgical procedures and better results. Our limited experience in benign soft-tissue tumours such as myxoma and giant-cell tumour of soft tissues has shown that cryosurgery might be a powerful tool for eradication of these tumours. The use of cryosurgery in recurrent schwannoma of peripheral nerves, chordoma, other sacral tumours, and in bone tumours where a peripheral nerve is involved (eg, proximal fibula) has shown that these nerves sometimes dysfunction after cryosurgery for up to 6 months; however, most patients have a complete recovery. Further study on the behaviour of nerve tissue during cryosurgery is warranted to optimise the temperature for tumour-cell kill and to reduce the period of nerve dysfunction Vol 6 January, 2005

9 Conflict of interest We declare no conflicts of interest. References 1 Arnott JM. Practical illustrations of the remedial efficiency of a very low anaesthetic temperature in cancer. Lancet 1850; 2: Holden HB. History and development of cryosurgery. In: Holden HB (ed). Practical cryosurgery. Chicago: Pitman Medical Publication, 1975: Cage AA, Greene GW, Neiders ME, et al. Freezing bone without excision. An experimental study -cell destruction and manner of regrowth in dogs. JAMA 1966; 196: Marcove RC, Miller TR. The treatment of primary and metastatic localized bone tumors by cryosurgery. Surg Clin N Am 1969; 49: Oeseburg HB. Cryosurgical treatment of different bone tumours. PhD thesis, University of Groningen, Netherlands, 1977: Schreuder HWB, Keijser LCM, Veth RPH, et al. (Benificial) effects of cryosurgical treatment in benign and low-grade malignant bone tumors. Ned Tijdschr Geneeskd 1999; 143: Gage A, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology 1998; 37: Bischof J, Christov K, Rubinsky. A morphological study of cooling rate response in normal and neoplastic human liver tissue: cryosurgical implications. Cryobiology 1993; 30: McGann LE, Yang HY, Walterson M. Manifestations of cell damage after freezing and thawing. Cryobiology 1988; 25: Fujikawa S. Freeze-fracture and etching studies on membrane damage on human erythrocytes caused by formation of intracellular ice. Cryobiology 1980; 17: Berger WK, Uhrik B. Freeze-induced shrinkage of individual cells and cell-to-cell propagation of intracellular ice in cell chains from salivary glands. Experientia 1996; 52: Miller RH, Mazur P. Survival of frozen-thawed human red cells as a function of cooling and warming velocities. Cryobiology 1976; 13: Rabb JM, Renaud ML, Brandt PA, et al. Effect of freezing and thawing on the microcirculation and capillary endothelium of the hamster cheek pouch. Cryobiology 1974; 11: Kuylenstierna R, Lundquist PG, Nathanson A. Early morphological changes in rabbit mandible after cryogenic application. Arch Otorhinolaryngol 1980; 226: Kreyberg L. Tissue damage due to cold. Lancet 1946; 1: Holden HB, McKelvie P. Cryosurgery in the treatment of head and neck neoplasia. Br J Surg 1972; 59: Gage AA, Baust JG. Cryosurgery for tumors. Technol Cancer Res Treat 2004; 3: Robinson D, Yassin M, Nevo Z. Cryotherapy of musculoskeletal tumors from basic to clinical results. Technol Cancer Res Treat 2004; 3: Keijser LCM, Schreuder HWB, Buma P, et al. Cryosurgery in long bones: an experimental study of necrosis and revitalization in rabbits. Arch Orthop Traum Surg 1999; 119: Gage AA, Guest K, Montes M, et al. Effect of varying freezing and thawing rates in experimental cryosurgery. Cryobiology 1985; 22: Schargus G, Winckler J, Schröder F, Schafer B. Cryosurgical devitalization and its regeneration. An experimental study with animals. J Maxillofac Surg 1975; 3: Gage AA, Greene GW, Neiders ME, et al. Freezing bone without excision. An experimental study -cell destruction and manner of regrowth in dogs. JAMA 1966; 196: Keijser LC, Schreuder HW, Boons HW, et al. Bone grafting of cryosurgically treated bone defects: experiments in goats. Clin Orthop 2002; 396: Malawer MM and Dunham W. Cryosurgery and acrylic cementation as surgical adjuncts in the treatment of aggressive (benign) tumors. Analysis of 25 patients below the age of 21. Clin Orthop 1991; 262: Aboulafia AJ, Rosenbaum DH, Sicard-Rosenbaum, et al. Treatment of large subchondral tumors of the knee with cryosurgery and composite reconstruction. Clin Orthop 1994; 307: Unni KK. Dahlin s bone tumors. 5th edn. General aspects and data on cases. Philadelphia: Lippincott-Raven, 1996: Dorfman HD, Czerniak B. Bone cancers. Cancer 1995; 5 (suppl): Bertoni F, Bacchini P, Hogendoorn PCW. Chondrosarcoma. In: Fletcher CDM, Unni KK, Mertens F (eds). Pathology and genetics in tumours of soft tissue and bone. World Health Organization classification of tumours. Lyon: IARC Press, 2002: Welkerling H, Werner M, Delling G. Histologic grading of chondrosarcoma. A qualitative and quantitative analysis of 74 cases of the Hamburg bone tumor register. Pathologe 1996; 17: Bjornsson J, McLeod RA, Unni KK, et al. Primary chondrosarcoma of long bones and limb girdles. Cancer 1998; 83: Kusuzaki K, Murata H, Takeshita H, et al. Usefulness of cytofluorometric DNA ploidy in distinguishing benign cartilaginous tumors from chondrosarcomas. Mod Pathol 1999; 12: Mirra JM, Gold R, Downs J, Eckhardt JJ. A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases. Clin Orthop 1985; 201: De Silva MV, Reid R. Chondroblastoma: varied histologic appearance, potential diagnostic pitfalls, and clinicopathologic features associated with local reccurence. Ann Diagn Pathol 2003; 7: Accadbled F, Brouchet A, Salmeron F, et al. Recurrent aggressive chondroblastoma: two cases and a review of the literature. Rev Chir Orthop Reparatrice Appar Mot 2001; 87: Bergh P, Kindblom LG, Gunterberg B, et al. Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer 2000; 88: Reid R, Banerjee SS, Sciot R. Giant-cell tumor. In: Fletcher CDM, Unni KK, Mertens F (eds). Pathology and genetics, tumours of soft tissue and bone. World Health Organization Classification of Tumours, Lyon: IARC Press, 2002: Bertoni F, Bacchini P, Staals EL. Malignancy in giant cell tumor of bone. Cancer 2003; 97: Masui F, Ushigome S, Fujii K. Giant cell tumour : a clinicopathological study of prognostic factors. Pathol Int 48: Sulh MA, Greco MA, Jiang T, et al. Proliferation index and vascular density of giant cell tumors of the bone: are they prognostic markers? Cancer 1996; 77: Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop 1986; 204: Schiller CH, Ritschl P, Windhager R, et al. Frequency of recurrence in phenolized and nonphenolized bone cavities following intralesional excisions of nonmalignant bone tumors. Z Orthop 1989; 127: Schreuder HW, Pruszczynski M, Veth RP, et al. Treatment of benign and low-grade malignant intramedullary chondroid tumours with curettage and cryosurgery. Eur J Surg Oncol 1998; 24: Marcove RC, Weis LD, Vaghaiwalla MR, et al. Cryosurgery in the treatment of giant cell tumors. A report of 52 consecutive cases. Clin Orthop 1978; 134: Marcove RC, Sheth DS, Takemoto S, et al. The treatment of aneurysmal bone cyst. Clin Orthop 1995; 311: Malawer MM, Bickels J, Meller I, et al. Cryosurgery in the treatment of giant cell tumor. Clin Orthop 1999; 2: Dwyer DM, Thorne AC, Healey JH, et al. Liquid nitrogen instillation can cause venous gas embolism. Anesthesiology 1990; 73: Schreuder HWB, van Beem HBH, Veth RPH. Venous gas embolism during cryosurgery for bone tumors. J Surg Oncol 1995; 60: Fisher AD, Williams DF, Bradley PF. The effect of cryosurgery on the strength. Br J Oral Surg 1978; 15: Sheth DS, Healey JH, Sobel M, et al. Giant cell tumor of the distal radius. J Hand Surg (Am) 1995; 20: Boons HW, Keijser LC, Schreuder HW, et al. Oncologic and functional results after treatment of giant cell tumors. Arch Orthop Trauma Surg 2002; 122: Vol 6 January,

10 51 Keijser LC, Schreuder HW, Boons HW, et al. Bone grafting of cryosurgically treated bone defects: experiments in goats. Clin Orthop 2002; 396: Heidenheim M, Jemec GBE. Side effects of cryotherapy. J Am Acad Dermatol 1991; 24: Seeger LL, Yao L, Eckardt JJ. Surface lesions. Radiology 1998; 5: Priolo F, Cerase A. The current role of radiography in the assessment of skeletal tumors and tumor-like lesions. Eur J Radiol 1998; 27 (suppl 1): S Campanacci M, Mercuri M, Gasbarrini A, et al. The value of imaging in the diagnosis and treatment tumors. Eur J Radiol 1998; 27 (suppl 1): S Vanel D, Verstraete KL, Shapeero LG. Primary tumors of the musculoskeletal system. Radiol Clin North Am 1997; 35: May DA, Good RB, Smith DK, et al MR imaging of musculoskeletal tumors and tumor mimickers with intravenous gadolinium: experience with 242 patients. Skeletal Radiol 1997; 26: Leung JC, Dalinka MK. Magnetic resonance imaging in primary bone tumors. Semin Roentgenol 2000; 35: Van der Woude HJ, Verstraete KL, Hogendoorn PCW, et al. Musculoskeletal tumors: does fast dynamic contrast-enhanced subtraction MR imaging contribute to the characterization? Radiology 1998; 208: Parkkola RK, Mattila KT, Heikkila JT, et al. Dynamic contrastenhanced MR imaging and MR-guided bone biopsy on a 0.23T open imager. Skeletal Radiol 2001; 30: Scarborough MT. The biopsy. Instr Course Lect 2004; 53: Lee MJ, Janzen DL, Munk PL, et al. Quantitative assessment of an MR technique for reducing metal artefact: application spin-echo imaging in a phantom. Skeletal Radiol 2001; 30: Van der Woude HJ, Vanderschueren G. Ultrasound in musculoskeletal tumors with emphasis on its role in tumor follow-up. Radiol Clin North Am 1999; 37: Richardson ML, Lough LR, Shuman WP, at al. MR-appearance of skeletal neoplasms following cryotherapy. Skeletal Radiol 1994; 23: Enneking WF. A system for the functional evaluation of the surgical management of muculoskeletal tumors. In: Enneking WF (ed). Limb salvage in musculoskeletal oncology. New York: Churchill Livingstone, 1987: Enneking WF, Dunham W, Gebhart MC. A system for the functional evaluation of reconstructive procedures after surgical treatment of tumors of the musculoskeletal system. Clin Orthop 1993; 286: Oda Y, Miura H, Tsuneyoshi M, et al. Giant cell tumor : oncological and functional results of long term follow-up. Jpn J Clin Oncol 1998; 28: Trieb K, Bitzan P, Lang S, et al. Recurrence of curetted and bone grafted giant cell tumours with and without adjuvant phenol therapy. Eur J Surg Oncol 2001; 27: Dabak N, Tomak Y, Piskin A, et al. Early results of a modified technique of cryosurgery. Int Orthop 2003; 27: Campanacci M, Baldini N, Boriani S, et al Giant cell tumor. J Bone Joint Surg 1987; 69: VanLoon CJM, Veth RPH, Pruszczynski M, et al. Chondrosarcoma : oncologic and functional results. J Surg Oncol 1994; 57: Wittig JC, Simpson BM, Bickels J, et al. Giant cell tumor of the hand: superior results with curettage, cryosurgery and cementation. J Hand Surg 2001; 26: Kollender Y, Meller I, Bickels J, et al. Role of adjuvant cryosurgery in intralesional treatment of sacral tumors. Cancer 2002; 97: Bickels J, Meller I, Shmookler B, et al. The role and biology of cryosurgery in the treatment tumors. Acta Orthop Scand 1999; 70: Robinson D, Halperin N, Nevo Z. Two freezing cycles ensure interface sterilization by cryosurgery during bone tumor resection. Cryobiology 2001; 43: Baust JG, Gage AA, Clarke D, et al. Cryosurgery a putative approach to molecular-based optimization. Cryobiology 2004; 48: Vol 6 January, 2005