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BACKGROUND■ Cryoablation is the therapeutic application of cold in situ toinduce tissue necrosis with curative intent. Cryoablation per-formed by direct pouring of liquid nitrogen is an effective adju-vant to curettage in the management of a large variety of bonetumors, including benign–aggressive, metastatic, and primarymalignant lesions. It is an intralesional procedure, which permitsthe avoidance of major resection and associated loss of function.■ Cryoablation is a very powerful technique. It weakens thebone surrounding the tumor cavity and, when not used judi-ciously, may cause additional soft tissue injuries. Awareness ofthese potential complications has led to refinement of surgicalpractices to include soft tissue protection, stable reconstruc-tion, the use of perioperative antibiotics, and enhancement ofrehabilitation protocols for gradual weight bearing. Thoseguidelines have resulted in a gratifyingly low rate of complica-tions and rendered this treatment a safe and reliable modality.■ It may be expected that cryoablation will no longer be theexclusive practice of a relatively small group of surgeons andthat it will eventually enjoy greater popularity in the not toodistant future.

Historical Aspects and Physiologic Background■ Although cryoablation had been used in the 1850s for themanagement of locally advanced carcinoma of the cervix, itsapplicability to the management of bone tumors was not as-sessed until more than a century later, in the classic 1966 ani-mal study by Gage et al,13 in which the femora of living mon-grel dogs were frozen by perfusing liquid nitrogen throughencircling latex coils. Liquid nitrogen, which has a boilingtemperature of �196°C, allowed rapid freezing of a 2-cm rimof bone around these coils. Using histopathologic studies andplain radiographs, the authors documented the occurrence oftissue necrosis and bone resorption that was associated withmechanical weakening and spontaneous fractures.13 Thesechanges, however, were followed by new bone formation thatdeveloped slowly, starting from the vital bone at the periphery:it was first observed at 2 months and reached its peak at6 months after freezing.13

■ Although only normal bone was investigated in their experi-ment, Gage et al speculated that cold allows for nonspecific celldestruction and may induce tumor kill as well. They further sug-gested the use of intralesional cryoablation in lieu of tumorresection or amputation.13 The use of this technique in the man-agement of human bone tumors was first reported in 1969.33

Following curettage of a metastatic bone lesion, Marcove andMiller33 poured liquid nitrogen into the tumor cavity with theintent of inducing tumor necrosis and avoiding the need for ex-tensive resection and reported having achieved both goals.■ Further studies confirmed and refined the initial findings ofGage et al13 and showed that temperatures between �21°Cand �60°C are needed to obtain cell necrosis; temperaturesbelow �60°C exerted no further lethality.18,28,33

■ A number of mechanisms have been found to be responsiblefor the tissue necrosis induced by cryoablation.12,15,22,26,28,41,42

These mechanisms can be grouped into two categories: immedi-ate and delayed.

■ Four mechanisms are involved in the immediate cytotoxi-city produced by cryoablation: (1) formation of ice crystalsand membrane disruption; (2) thermal shock; (3) dehydra-tion and toxic effects of electrolyte changes; and (4) denatu-ration of cellular proteins. The formation of intracellular icecrystals is considered as being the main mechanism of imme-diate cellular necrosis.■ The two mechanisms most likely responsible for the de-layed, progressive necrosis that is observed followingcryoablation and for the problems associated with subse-quent repair of frozen tissue are (1) the damage to the mi-crovascular circulation and (2) vascular stasis.12,28

■ During cryoablation, ice crystals first occur in the extracel-lular spaces. The withdrawal of water from the system intothese crystals creates a hyperosmotic extracellular environ-ment, which, in turn, draws water from the cells. As theprocess continues, these crystals grow, the cells shrink and de-hydrate, electrolyte concentration is increased, and mem-branes and cell constituents are damaged.12,17,41 Becauserapid freezing, such as that achieved by direct pour of liquidnitrogen, does not allow sufficient time for the withdrawal ofwater from the cells, intracellular ice crystals are formed si-multaneously.■ Conversely, a slow thaw will cause intracellular recrystal-lization of the already formed crystals and membrane disrup-tion, whereas a rapid thaw will not.2,7,41,48

■ Repeated freeze–thaw cycles also increase the extent of tis-sue necrosis because of the improved cold conductivity follow-ing the first cycle.11,12,15 Therefore, repeated cycles of rapidfreezing and spontaneous thaw achieve the maximal effect ofcell necrosis.■ Histologically, the most dramatic effect of cryoablation ison the appearance of the bone marrow: a rim of 1 to 2 cm ofextensive necrosis with minimal inflammatory response ap-pears following direct pour of liquid nitrogen.13,29,39,41 This isfollowed by liquefaction and progressive fibrosis. Large, thick-ened, and thrombosed vessels occasionally are seen as well.

INDICATIONSHistologic Diagnoses■ Benign–aggressive bone tumors

■ Giant cell tumor■ Aneurysmal bone cyst■ Simple bone cyst■ Fibrous dysplasia■ Enchondroma■ Chondroblastoma■ Eosinophilic granuloma

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■ Osteoblastoma■ Chondromyxoid fibroma

■ Low-grade sarcomas of bone■ Low-grade chondrosarcoma

■ Metastatic tumors

Morphologic Criteria■ Cryoablation is appropriate for periarticular and sacral le-sions in which the circumferential rim of the cortex that

remains after tumor removal can hold liquid material and isadequate to ensure a mechanically stable reconstruction.

SURGICAL MANAGEMENT■ Cryosurgical ablation is carried out in five stages: (1) tumorexposure; (2) thorough curettage; (3) high-speed burr drillingof the tumor cavity; (4) cryoablation; and (5) mechanicalreconstruction.5,6,27

DIRECT POUR LIQUID NITROGEN■ When technically possible, a pneumatic tourniquet is

used during the procedure to decrease local bleedingand prevent blood from acting as a heat sink and posinga thermal barrier to cryoablation.

■ A large cortical window the size of the longest longitu-dinal dimension of the tumor is made after exposure ofthe involved bone. It must be elliptical, with its axisparallel to the long axis of bone, to reduce the stress ris-ing effect (TECH FIG 1A–C).

■ All gross tumor material is removed with hand curettes(TECH FIG 1D–E). This is followed by high-speed burrdrilling of all remaining macroscopic disease and thewalls of the tumor cavity (TECH FIG 1F).

■ Bony perforations are identified and sealed withGelfoam (Upjohn, Kalamazoo, MI) before introductionof the liquid nitrogen. The neurovascular bundle andfasciocutaneous flaps are protected by mobilization andby shielding (with surgical pads) from direct contactwith the liquid nitrogen, after which cryoablation isperformed.

TECH FIG 1 • A. Plain radiograph showing aneurysmal bone cyst of the proximalhumerus. B. The tumor site is widely exposed by a deltopectoral incision, and fascio-cutaneous flaps are mobilized to expose the entire extent of the tumor. C. A largecortical window the size of the longest longitudinal dimension of the tumor is made. D. Plain radiograph showing giant cell tumor of the distal femur. E. The tumor is firstremoved with hand curettes. This should be meticulously performed, leaving onlyresidual microscopic disease in the tumor cavity. (continued)

A B C

D

E

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TECH FIG 1 • (continued) F. Curettage is followed by high-speed burr drilling.

F

■ The traditional technique of cryoablation entails directpour of liquid nitrogen through a stainless steel funnel intothe tumor cavity, taking care to fill the entire cavity (TECHFIG 2). Thermocouples are used to monitor the freezewithin the cavity, cavity wall, adjacent soft tissues, and anarea 1 to 2 mm from the periphery of the cavity. The sur-rounding soft tissues are irrigated continuously with warmsaline solution to decrease the possibility of thermal injury.

■ Freezing (boiling of liquid nitrogen) lasts 1 to 2 minutesand is proportional to the volume of poured liquid nitro-gen. It is followed by spontaneous thaw, which occursover 3 to 5 minutes. The cycle is considered completeonce the temperature of the cavity rises above 0°C. Thecavity is irrigated with saline after two freeze–thaw cy-cles have been carried out. At this point, the process ofreconstructing the tumor cavity begins.

■ Reconstruction includes the use of internal fixation andthe use of polymethylmethacrylate (PMMA; TECH FIG 3).Subchondral surfaces are reinforced with autologousbone graft before cementation.

CLOSED CRYOABLATION WITH ARGON GAS■ Cryoablation using direct pour of liquid nitrogen has

several technical drawbacks. First, after it has beenpoured, there is no control of the overall freezingtime or of the temperature at different sites within thetumor cavity. Second, it is a gravity-dependent proce-dure, ie, the poured liquid cannot reach corners ofthe tumor cavity that are positioned above the fluidlevel.

■ In response to these problems, closed cryoablation usingargon gas was developed and became available in thelate 1990s.4 This approach entails filling the tumor cavitywith a gel medium, inserting metal probes into the gel,and executing computer-controlled delivery of argon gasthrough the metal probes.

■ Argon gas serves as the freezing agent, and the sur-rounding gel acts as a conducting medium, which distrib-utes the low temperature equally throughout the tumorcavity (TECH FIGS 4, 5, and 6).

■ Computer-controlled delivery of argon gas allows deter-mination of both the desired temperature throughoutthe tumor cavity and the overall freezing time, and theuse of a viscous gel enables filling of any shape of tumorcavity, regardless of gravity considerations (TECH FIG 7).

TECH FIG 2 • The traditional technique of cryoablation performed using di-rect pour of liquid nitrogen. A. Stainless steel can and funnels. B. The sur-rounding soft tissues are protected with surgical pads. C. Direct pour of liq-uid nitrogen into the tumor cavity, which is irrigated continuously with warmsaline throughout the freezing and thawing processes (5 minutes alto-gether). D. Direct pour of liquid nitrogen and protection of the surroundingsoft tissues.

A

B C

D

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TECH FIG 3 • Reconstruction includes cemented hardware and reinforcement of subchondral surfaces with autolo-gous bone graft. This principle of reconstruction is applied in all anatomic locations: proximal femur (A), distalfemur (B), proximal tibia (C), distal tibia (D), distal radius (E), and proximal ulna (F).

A B C

D

F

E

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TECH FIG 4 • A. Different sizes of metal probes used for delivery of argongas. B. The tumor cavity filled with gel medium and the metal probewithin it. C. The gel freezes and creates an ice ball within a few secondsafter perfusion of the argon gas through the probe.

A B

C

A

B C

D E

TECH FIG 5 • A. Plain radiographshowing a giant cell tumor of theproximal tibia. B. Curved incisionalong the lateral tibial metaphysis. C. Curettage. D. High-speed burrdrilling. E. An ice ball is formedaround the tip of the probes on per-fusion of argon gas.

TECH FIG 6 • A. Recurrent low-grade chondrosarcoma of the distal radius. B. Tumor curettage. C. High-speed burrdrilling. (continued)

A B C

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TECH FIG 6 • (continued) D. The tumor cavityis filled with gel. E. Cryoablation.D E

A

B

TECH FIG 7 • Cryoablation of the proximal ulna(A) and the fourth toe (B) using the closed,argon-based system. It would have been difficultto freeze these sites with direct pour of liquidnitrogen due to the relatively large size of thefunnels.

PEARLS AND PITFALLSSurgery ■ Mobilization of the neurovascular bundle and surrounding soft tissues

■ Adequately large cortical window■ Meticulous curettage followed by high-speed burr■ Soft tissue protection and warming throughout cryoablation■ Reconstruction of the tumor cavity with cemented hardware and of the subchondral surface with autologous

bone graft

Postoperative ■ Protected weight bearing postoperatively

POSTOPERATIVE CARE■ Routine perioperative prophylactic antibiotics are adminis-tered for 3 to 5 days. Patients with lesions of the lowerextremities are kept non–weight bearing for 6 weeks. Plain ra-diographs are then obtained to rule out fracture and establishbone graft incorporation. Gradual weight bearing is allowedif healing has progressed satisfactorily.

OUTCOMES■ By far the most extensive experience with cryoablation hasinvolved giant cell tumor of bone, a benign–aggressive primarybone tumor. Two thirds of these lesions occur in the third orfourth decades of life, and, in most cases, they are located in

the metaphyseal-epiphyseal region of long bones around thearticular cartilage.19 Because wide excision of such tumorswould cause major loss of function due to their proximity tothe joint, it had been common practice to opt for intralesionalprocedures, but the rate of local recurrence, mainly after curet-tage, was unacceptably high (ie, 40%–55%).8,16,21,43

■ The use of cryoablation with liquid nitrogen, as an adjuvantto curettage and high-speed burr drilling, substantially loweredthe recurrence rate. Malawer et al27 reported a 2.3% recurrencerate among 86 patients treated primarily with cryoablation.They reported good-to-excellent functional outcome in 92%percent of the patients (FIG 1).27 Because cryoablation providesa nonselective mechanism for cell destruction, it is not surpris-ing that similar rates of local tumor control and associated good

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functions were reported with other benign–aggressive and ma-lignant tumors.3,4,9,14,23–25,28,30,31,34,35,37,38,40,44–46,49

COMPLICATIONS■ Gage et al13 observed that cryoablation is a double-edgedsword, ie, that it induces tumor necrosis with similar injury tothe surrounding normal tissues. This potential drawback ini-tially was underestimated by surgeons who pioneered the appli-cation of this technique in clinical practice. Inadequate protec-tion of soft tissues, lack of mechanical fixation, and failure touse perioperative antibiotics resulted in unacceptably high ratesof fractures, soft tissue injury, infections, and neurapraxias.32

■ Those complications gave cryoablation its bad reputationand motivated surgeons to refine the surgical technique to in-clude concomitant soft tissue mobilization and protection, sta-ble reconstruction with cemented internal fixation devices, andthe use of perioperative antibiotics. As a result, the same au-thors reported a later series of patients with a significantly re-duced rate of those complications.39,52

■ Postoperative fractures have been a devastating complicationof cryoablation (FIG 2A,B). They were considered pathologi-cal because they occurred through a mechanically weakenedbone and following a minor trauma.4,20,27,33,39 These fractureshealed slowly (over a period of 3 to 9 months) and were asso-ciated with a significant loss of function. Lack of stable fixationand early weight bearing were shown to be the important fac-tors leading to these fractures, and the treatment protocol waschanged accordingly: the consensus was that cryoablation mustbe followed by stable reconstruction that includes internal fix-ation reinforced with PMMA and a strict rehabilitation proto-col of gradual weight bearing.27,32,39 This regimen resulted in aminimal rate of postoperative fractures, as reported in seriespublished from the 1990s to date.4,24,27,44,46,49,50

■ When such postoperative fractures do occur, surgical inter-vention usually is not required. The fracture lines invariablyare along the internal fixation device, so the fracture is not sig-nificantly displaced, and immobilization and avoidance ofweight bearing usually are sufficient for treatment. Infectionsand flap necrosis also have become rare complications due tomobilization and protection of soft tissues prior to freezingand the use of perioperative antibiotics.■ Mobilization of the neurovascular bundle and surroundingsoft tissues away from the tumor site, as well as the use of pe-rioperative antibiotics, has led to low rates of infections, ther-mal injuries, and nerve palsies (FIG 2C). When the latter dooccur, the neurologic damage usually is transient and healsspontaneously. Cryoablation also was shown to be associatedwith minimal damage to the adjacent articular cartilage, withdegenerative changes reported in less than 3% of cases in alarge series of patients.27

FIG 1 • Full flexion of the knee in a 54-year-old man 3 monthsfollowing cryoablation of a chondrosarcoma of the lateralfemoral condyle. It would have been difficult to achieve such arange and muscle strength after the resection of the distalfemur that otherwise would have been offered to this patient.

FIG 2 • A. Plain radiograph showing pathological frac-ture of the proximal tibia following cryoablation and onweight bearing. Reconstruction following cryoablationin that patient consisted of autologous bone graft only.B. The wide collapse and destruction of the articularsurface made resection of the proximal tibia and recon-struction with endoprosthesis inevitable. C. Thermalinjury to the leg due to spillage of liquid nitrogen. Thesoft tissues apparently were not well protected in thispatient during freezing. This complication is rare whenadequate padding and warming with saline are carriedout. It is even more uncommon when using the closedargon-based system, which does not involve any pouredfluid whatsoever.A B

C

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■ Cryoablation achieves best local tumor control when ap-plied for microscopic disease and in tumors that have notcaused major cortical destruction and invasion into the sur-rounding soft tissues. Any compromise of either of these crite-ria ultimately may result in local tumor recurrence. Better caseselection, adequate curettage, and meticulous burr-drillinghave led to a drop in local recurrence rates, to less than 5% inmost series.4,24,27,44,46,47,49,51 A second cryoablative procedureis curative in most local recurrences.1,25,27,33,36,44,49–51

■ Venous gas embolism is a rare complication of open cryoab-lation with liquid nitrogen, having been reported in only 4cases.10,46,47 Liquid nitrogen rapidly produces nitrogen bub-bles (N2) at room temperature. Although most of the gas exitsinto the atmosphere through the surgical wound, a consider-able amount nevertheless is pushed into the pulmonary circu-lation under the influence of the pressure caused by boiling ofliquid nitrogen in the bony cavity, and exhaled.10,47 It usuallymanifests intraoperatively with decreased O2 saturation leveland end-tidal CO2, associated with a drop in blood pressureand a rise in the heart rate.47 These emboli usually resolvecompletely with early detection, discontinuation of nitrousoxide administration, and support with oxygen.47

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36. Marcove RC, Sheth DS, Brien EW, et al. Conservative surgeryfor giant cell tumors of the sacrum: the role of cryosurgery as a supple-ment to curettage and partial excision. Cancer 1994;74:1253–1260.

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40. Marcove RC, Zahr KA, Huvos AG, Ogihara W. Cryosurgery in os-teogenic sarcoma: report of three cases. Cancer 1984;10:52–60.

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simple bone cysts in children with curettage and cryosurgery. JPediatr Orthop 1997;17:814–820.

45. Schreuder HW, Pruszczynski M, Lemmens JA, Veth RP. Eosinophilicgranuloma of bone: results of treatment with curettage, cryosurgery,and bone grafting. J Pediatr Orthop B 1998;7:253–256.

46. Schreuder HW, Pruszczynski M, Veth RP, Lemmens JA. Treatment ofbenign and low-grade malignant intramedullary chondroid tumourswith curettage and cryosurgery. Eur J Surg Oncol 1998;24:120–126.

47. Schreuder HW, van Beem HB, Veth RP. Venous gas embolism duringcryosurgery for bone tumors. J Surg Oncol 1995;60:196–200.

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49. Schreuder HW, Veth RP, Pruszczynski M, et al. Aneurysmal bonecysts treated by curettage, cryotherapy and bone grafting. J BoneJoint Surg Br 1997;79B:20–25.

50. Segev E, Kollender Y, Bickels J, et al. Cryosurgery in fibrous dyspla-sia. Good result of a multimodality protocol in 16 patients. ActaOrthop Scand 2002;73:483–486.

51. Sheth DS, Healey JH, Sobel M, et al. Giant cell tumor of the distal ra-dius. J Hand Surg Am 1995;20A:432–440.

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