BACKGROUND

 

 

Cryoablation is the therapeutic application of cold in situ to induce tissue necrosis with curative intent. Cryoablation of bone tumors by direct pour of liquid nitrogen is an effective adjuvant to curettage in the management of a large variety of bone tumors including benign aggressive, metastatic, and primary malignant lesions. It is an intralesional procedure, which enables the avoidance of major resection and associated loss of function.

 

It is a very powerful technique that weakens the bone surrounding the tumor cavity and may, when not used judiciously, cause additional soft tissue injuries. Awareness of these potential complications has led to refinement of surgical practices to include soft tissue protection, stable reconstruction, and the use of perioperative antibiotics and enhancement of rehabilitation protocols for gradual weight bearing. Those guidelines resulted in a gratifying low rate of complications and rendered this treatment a safe and reliable modality.

 

It may be expected that cryoablation will no longer be the exclusive practice of a relatively small group of surgeons and that it will eventually enjoy greater popularity in the not too distant future.

 

Historical Aspects and Physiologic Background

 

Although it had been used in the 1850s for the management of locally advanced carcinoma of the cervix, the applicability of cryoablation in the management of bone tumors was not assessed until more than a century

later, in the classic 1966 animal study by Gage et al13 in which the femora of living mongrel dogs were frozen by perfusing liquid nitrogen through encircling latex coils. Liquid nitrogen, which has a boiling temperature of -196 °C, allowed rapid freezing of a 2-cm rim of bone around these coils. Using histopathologic studies and plain radiographs, the authors documented the occurrence of tissue necrosis and bone resorption that was

associated with mechanical weakening and spontaneous fractures.13 These changes, however, were followed by new bone formation that developed slowly, starting from the vital bone at the periphery: It was first

observed at 2 months and reached its peak at 6 months after freezing.13

 

Although only normal bone was investigated in their experiment, Gage et al13 speculated that cold allows for nonspecific cell destruction and may induce tumor kill as well. They further suggested the use of intralesional cryoablation in lieu of tumor resection or amputation. The use of this technique in the management of human

bone tumors was first reported in 1969.33 Following curettage of a metastatic bone lesion, those authors poured liquid nitrogen into the tumor cavity with the intent of inducing tumor necrosis and avoiding the need for extensive resection and reported having achieved both goals.

 

Further studies confirmed and refined the initial findings of Gage et al13 and showed that temperatures between -21 °C and -60 °C are needed to obtain cell necrosis, whereas temperatures below -60 °C exerted no

further lethality.18,28,33

 

It also emerged that a number of mechanisms are responsible for the tissue necrosis induced by cryoablation.12,15,22,26,28,41,42 These mechanisms can be grouped into two categories: immediate and delayed.

 

Four mechanisms are involved in the immediate cytotoxicity produced by cryoablation: (1) formation of ice crystals and membrane disruption, (2) thermal shock, (3) dehydration and toxic effects of electrolyte changes, and (4) denaturation of cellular proteins. The formation of intracellular ice crystals is considered as being the main mechanism of immediate cellular necrosis.

 

The two mechanisms most likely responsible for the delayed, progressive necrosis that is observed following cryoablation and for the problems associated with subsequent repair of frozen tissue are the damage to the microvascular circulation and vascular stasis.12,28

 

During cryoablation, ice crystals first occur in the extracellular spaces. The withdrawal of water from the system into these crystals creates a hyperosmotic extracellular environment, which, in turn, draws water from the cells. As the process continues, these crystals grow, the cells shrink and dehydrate, electrolyte

concentration is increased, and membranes and cell constituents are damaged.12,17,41 Rapid freezing, such as that achieved by direct pour of liquid nitrogen, does not allow sufficient time for the withdrawal of water from the cells and so intracellular ice crystals are formed simultaneously. Conversely, a slow thaw will cause intracellular recrystallization of the already formed crystals and membrane disruption, whereas a rapid thaw

will not.2,7,41,48 Repeated freeze-thaw cycles will also increase the extent of tissue necrosis because of the improved cold conductivity following the first cycle.11,12,15 Therefore, repeated cycles of rapid freezing and spontaneous thaw will achieve the maximal effect of cell necrosis.

 

Histologically, the most dramatic effect of cryoablation is on the appearance of the bone marrow: a rim of 1 to 2 cm of extensive necrosis with minimal inflammatory response appears, following direct pour of liquid nitrogen.13,29,39,41 This is followed by liquefaction and progressive fibrosis. Large, thickened, and thrombosed

vessels are occasionally seen as well.

 

 

P.69

 

INDICATIONS

Histologic Diagnoses

Benign aggressive bone tumors Giant cell tumor

Aneurysmal bone cyst

Simple bone cyst Fibrous dysplasia Enchondroma Chondroblastoma Eosinophilic granuloma Osteoblastoma Chondromyxoid fibroma

Low-grade sarcomas of bone

 

Low-grade chondrosarcoma Metastatic tumors

Morphologic Criteria

Cryoablation is appropriate for periarticular and sacral lesions in which the circumferential rim of the cortex that remained after tumor removal could hold liquid material and was sufficient for ensuring a mechanically stable reconstruction.

 

 

SURGICAL MANAGEMENT

 

There are five stages in carrying out cryosurgical ablation5,6,27:

 

 

 

Tumor exposure Thorough curettage

 

 

High-speed burr drilling of the tumor cavity Cryoablation

 

Mechanical reconstruction

 

Cryoablation using direct pour of liquid nitrogen has several technical drawbacks.

 

 

First, after it has been poured, there is no control of the overall freezing time or of the temperature at different sites within the tumor cavity.

 

Second, it is a gravity-dependent procedure, that is, the poured liquid cannot reach corners of the tumor cavity that are positioned above the fluid level.

 

To solve these problems, closed cryoablation using argon gas was developed and became available in the late 1990s.4

 

Both techniques are considered in the following text.

 

 

TECHNIQUES

• Direct Pour of Liquid Nitrogen

Exposure

When technically possible, a pneumatic tourniquet is used during the procedure to decrease local bleeding and prevent blood from acting as a heat sink and posing as a thermal barrier to cryoablation.

A large cortical window the size of the longest longitudinal dimension of the tumor is made after exposure of the involved bone. It has to be elliptical with its axis parallel to the long axis of bone to reduce the stress rising effect (TECH FIG 1).

Curettage and Burr Drilling

All gross tumor material is removed with hand curettes (TECH FIG 2A,B).

This is followed by high-speed burr drilling of all remaining macroscopic disease and the walls of the tumor cavity (TECH FIG 2C,D).

Bony perforations are identified and sealed with Gelfoam (Upjohn, Kalamazoo, MI) before introduction of the liquid nitrogen. Neurovascular bundle and fasciocutaneous flaps are protected by mobilization and by

shielding (with surgical pads) from direct contact with the liquid nitrogen, after which cryoablation is performed.

 

 

 

TECH FIG 1 • Plain radiograph (A) and magnetic resonance imaging (MRI) showing (B) giant cell tumor of the proximal tibia. (continued)

 

 

P.70

 

 

 

 

TECH FIG 1 • (continued) C. A large incision is planned to allow wide exposure of the tumor cavity. D.

Fasciocutaneous flaps are mobilized and the cortical bone overlying the tumor cavity is exposed.

 

 

 

TECH FIG 2 • A. A large cortical window the size of the longest longitudinal dimension of the tumor is made and the tumor is first removed with hand curettes. B. Illustration showing tumor curettage. This should be meticulously performed, leaving only residual microscopic disease in the tumor cavity. C. Curettage is followed by high-speed burr drilling. D. Illustration showing high-speed burr drilling of a tumor cavity.

 

 

P.71

Cryoablation

 

The traditional technique of cryoablation entails direct pour of liquid nitrogen through a stainless steel funnel into the tumor cavity, taking care to fill the entire cavity (TECH FIG 3A,B). Thermocouples are used to monitor the freeze within the cavity, cavity wall, adjacent soft tissues, and an area 1 to 2 mm from the periphery of the cavity. The surrounding soft tissues are continuously irrigated with warm saline solution to decrease the possibility of thermal injury.

 

Freezing (boiling of liquid nitrogen) lasts 1 to 2 minutes and is proportional to the volume of poured liquid nitrogen. It is followed by spontaneous thaw that occurs over 3 to 5 minutes. The cycle is considered complete once the temperature of the cavity rises more than 0°C. The cavity is irrigated with saline after two freeze-thaw cycles have been carried out (TECH FIG 3C-E). At this point, the process of reconstructing the tumor cavity begins.

 

 

 

TECH FIG 3 • The traditional technique of cryoablation using direct pour of liquid nitrogen. A. Stainless steel can and funnels. B. The surrounding soft tissues are protected with surgical pads. C. Direct pour of liquid nitrogen into the tumor cavity, which is continuously irrigated with warm saline throughout the freezing and thawing processes (˜5 minutes altogether). D. Illustration showing direct pour of liquid nitrogen and protection of the surrounding soft tissues. E. Intraoperative photograph following curettage, high-speed burr, and cryosurgery.

 

Reconstruction

 

Reconstruction includes the use of internal fixation and the use of polymethylmethacrylate (PMMA). Subchondral surfaces are reinforced with autologous bone graft before cementation (TECH FIG 4).

 

P.72

 

 

 

TECH FIG 4 • Reconstruction includes cemented hardware and reinforcement of subchondral surfaces with autologous bone graft. This principle of reconstruction is applied in all anatomic locations: Intraoperative photos (A) and (B) showing intramedullary rods and then rods with cementation, and postoperative radiographs of fixation for (C) proximal femur, (D) distal femur, (E) proximal tibia, (F) distal tibia, (G) proximal ulna, and (H) distal radius.

 

 

 

• Closed Cryoablation with Argon Gas

P.73

 

This approach entails filling the tumor cavity with a gel medium, inserting metal probes into the gel (TECH FIG 5), and executing computer-controlled delivery of argon gas through the metal probes.

 

Argon gas serves as the freezing agent and the surrounding gel acts as a conducting medium, which distributes the low temperature equally throughout the tumor cavity (TECH FIGS 6 and 7).

 

 

 

TECH FIG 5 • A. Different sizes of metal probes used for delivery of argon gas. B. Illustration showing the tumor cavity filled with gel medium and the metal probe within it. C. The gel freezes and creates an ice ball within a few seconds after perfusion of the argon gas through the probe.

 

 

 

TECH FIG 6 • A. Plain radiograph showing giant cell tumor of the proximal tibia. B. Curved incision along the lateral tibial metaphysis. C. Curettage. D. High-speed burr drilling. E. An ice ball is formed around the tip of the probes upon perfusion of argon gas.

 

Computer-controlled delivery of argon gas allows determination of the desired temperature throughout the tumor cavity as well as of the overall freezing time, and the use of a viscous gel enables filling of any shape of tumor cavity, regardless of gravity considerations (TECH FIG 8).

 

P.74

 

 

 

TECH FIG 7 • A. Photograph showing recurrent low-grade chondrosarcoma of the distal radius. B. Tumor curettage. C. High-speed burr drilling. D. The tumor cavity is filled with gel. E. Cryoablation.

 

 

 

TECH FIG 8 • Cryoablation of the fourth toe using the closed, argonbased system. It would have been difficult to freeze these sites with direct pour of liquid nitrogen due to the relatively large size of the funnels.

 

 

 

P.75

 

PEARLS AND PITFALLS

Surgical

considerations

• 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

Rehabilitation

• Protected weight bearing postoperatively

 

POSTOPERATIVE CARE

 

 

Routine perioperative prophylactic antibiotics are administered for 3 to 5 days. Patients with lesions of the lower extremities are kept non-weight bearing for 6 weeks.

 

Plain radiographs are then obtained to rule out fracture and establish bone graft incorporation.

 

Gradual weight bearing is allowed if healing had progressed satisfactorily.

OUTCOMES

By far, the most extensive experience with cryoablation has involved giant cell tumor of bone, a benign aggressive primary bone tumor. Two-thirds of these lesions occur in the third or fourth decades of life and, in most cases, are located in the metaphyseal-epiphyseal region of long bones around the articular

cartilage.19 Because wide excision of such tumors would cause major loss of function due to their proximity to the joint, it had been common practice to opt for intralesional procedures, but it emerged that the rate of local recurrence, mainly after curettage, was unacceptably high, that is, 40% to 55%.8,16,21,43

The use of cryoablation with liquid nitrogen as an adjuvant to curettage and high-speed burr drilling

substantially lowered the recurrence rate. Malawer et al27 reported a 2.3% recurrence rate among 86 patients treated primarily with cryoablation. Good to excellent functional outcome was reported in 92% of

the patients (FIG 1).27 Because cryoablation provides a nonselective mechanism for cell destruction, it is not surprising that similar rates of local tumor control and associated good functions were reported with other benign aggressive and malignant tumors.3,4,9,14,23,24,25,28,30,31,34,35,37,38,40,44,45,46,49

 

 

 

COMPLICATIONS

The observation made by Gage et al13 that cryoablation is a double-edged sword, that is, that it induces tumor necrosis with similar injury to the surrounding normal tissues, was initially underestimated by surgeons who pioneered the application of this technique in clinical practice. Inadequate protection of soft tissues, lack of mechanical fixation, and failure to use perioperative antibiotics resulted in

unacceptably high rates of fractures, soft tissue injury, infections, and neurapraxias.32

Those complications gave cryoablation its bad reputation and motivated refinements of the surgical technique to include concomitant soft tissue mobilization and protection, stable reconstruction with cemented internal fixation devices, and the use of perioperative antibiotics. As a result, the same authors

reported a later series of patients with a significantly reduced rate of those complications.39,52

Postoperative fractures have been a devastating complication of cryoablation (FIG 2). They were considered pathologic because they occurred through a mechanically weakened bone and following a minor trauma.4,20,27,33,39 These fractures healed slowly (over a period of 3 to 9 months) and were

associated with a significant loss of function. Lack of stable fixation and early weight bearing were shown

to be the important determinants of these fractures, and the treatment protocol was changed accordingly: The consensus was that cryoablation must be followed by stable reconstruction that includes internal fixation reinforced with PMMA and a strict rehabilitation protocol of gradual weight bearing.27,32,39 This

regimen resulted in a minimal rate of postoperative fractures, as reported in the series published from the

1990s to date.4,24,27,44,46,49,50

 

When such postoperative fractures do occur, surgical intervention is generally not required because the fracture lines are invariably along the internal fixation device and so are not significantly displaced, whereupon immobilization and avoidance of weight bearing are usually sufficient. Infections and flap necrosis have also become rare complications due to mobilization and protection of soft tissues prior to freezing and to the use of perioperative antibiotics.

 

 

 

FIG 1 • Full flexion of the knee in a 54-year-old male 3 months following cryoablation of a chondrosarcoma of the lateral femoral condyle. It would have been difficult to achieve such a range and muscle strength after the distal femur resection that would have otherwise been offered to this patient.

 

 

P.76

 

 

 

FIG 2 • A. Plain radiograph showing pathologic fracture of the proximal tibia following cryoablation and upon weight bearing. Reconstruction following cryoablation in that patient consisted solely of autologous bone graft only. B. The wide collapse and destruction of the articular surface made resection of the proximal tibia and reconstruction with endoprosthesis inevitable.

 

 

Mobilization of the neurovascular bundle and surrounding soft tissues away from the tumor site, as well as the use of perioperative antibiotics, resulted in low rates of infections, thermal injuries, and nerve palsies (FIG 3). When the latter do occur, the neurologic damage is usually transient and heals spontaneously. Cryoablation was also shown to be associated with a minimal damage to the adjacent articular cartilage with degenerative changes having occurred in less than 3% in a large series of patients

(FIG 4).27

 

Cryoablation achieves best local tumor control when applied on microscopic disease and in tumors, which have not caused major cortical destruction and invasion into the surrounding soft tissues. Any compromise of one of these criteria may ultimately result in a local tumor recurrence. Better case selection, adequate curettage, and meticulous burr drilling have led to a drop in local recurrence rates to

less than 5% in most series.4,24,27,44,46,47,49,51 A second cryoablative procedure is curative in most cases of local recurrence.1,25,27,33,36,44,49,50,51

 

 

 

FIG 3 • Thermal injury to the leg due to spillage of liquid nitrogen. The soft tissues were apparently not well protected in this patient during freezing. This complication is rare when adequate padding and warming with saline are carried out. It is even rarer when using the closed argon-based system that does not involve any poured fluid whatsoever.

 

 

 

FIG 4 • (A) Anteroposterior and (B) lateral radiographs of the knee joint showing considerable degenerative changes of the tibial articular cartilage eight years following cryoablation of giant cell tumor occupying the proximal tibia.

 

 

Venous gas embolism is a rare complication of open cryoablation with liquid nitrogen, having been reported in only four cases.10,46,47 Liquid nitrogen rapidly produces nitrogen bubbles (N2) at room temperature. Although most of the gas exits into the atmosphere through the surgical wound, a considerable amount is nevertheless pushed into the pulmonary circulation under the influence of the

pressure due to boiling of liquid nitrogen in the bony cavity and exhaled.10,47 It is usually manifested intraoperatively with decreased oxygen saturation level and end-tidal carbon dioxide (CO2), associated

with a drop in blood pressure and a rise in the heart rate.47 These emboli usually resolve completely with early detection, discontinuation of nitrous oxide administration, and support with oxygen.47

 

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