TECHNOLOGY, EQUIPMENT, AND CRYOBIOLOGY
Technology and Equipment
In general, cryoequipment has 3 components: the console, cryogen, and cryoprobe. The console provides monitoring of cryopressure, probe tip temperature, and length of treatment application. Nitrous oxide or carbon dioxide and liquid nitrogen can be used as cryogens to achieve −70°C to −89°C and −196°C temperatures in seconds, respectively. The technology depends on the Joule-Thompson effect in which compressed gas exits at a high flow, expands rapidly, and creates low temperatures leading to adhesion of the tissue to the probe. Cessation of flow and pressure decrease is followed by release of heat and defrosting. The tissue can be extracted during the freeze-thaw cycle. Cryoprobes can be rigid, semi-rigid, and flexible with tip diameters of 1.9, 2.4, and 5.5 mm for all and length of 90 cm and 50 cm to 60 cm for the flexible probes and rigid probes, respectively (Spembly Medical Ltd, UK and ERBE, Germany). Straight probes are ideal for lesions in the trachea, main bronchi, and lower lobes and used for transbronchial biopsies; angled probes are designed to fit upper lobes. Probe diameter is directly proportional with treatment area effect. Although there is no adverse effect of low temperatures to the rigid bronchoscope, flexible bronchoscopes can be damaged by ice droplets forming in the working channel.
The destructive effects of cryotherapy are 2-fold: cellular injury and vascular injury. Although cellular injury is immediate, vascular injury is largely delayed because of progressive failure of microcirculation, ultimate vascular stasis, and subsequent necrosis.
Cellular injury results from deleterious effects of the cooling and warming cycles. As the temperature falls to below 0°C, water crystallizes first in extracellular spaces that creates a hyperosmotic extracellular environment resulting in cellular dehydration at 0°C to −20°C. Given enough time in this dehydrated state, the increased intracellular electrolyte concentration is often sufficient to destroy the cells. When temperature drops below −20°C intracellular ice forms, which is almost always lethal. During thawing, ice crystals fuse to form larger crystals, a process called recrystallization, which occurs at temperatures warmer than −40°C. The ice melts first in extracellular environment causing hypotonicity that results in more free water entering the damaged cells leading to cell membrane rupture.1–4
During the initial freeze cycle, the tissue responds with vasoconstriction, with a resultant decrease in blood flow that eventually ceases when freezing is complete. During thawing, the circulation returns with compensatory vasodilatation. However, the endothelial damage from cryotherapy results in increased permeability of the capillary walls, edema, platelet aggregation, and microthrombus formation. Progressive circulatory stagnation results over the ensuing hours. Many small vessels become completely thrombosed 3 to 4 hours after thawing. Together, these effects culminate in tissue necrosis.5–9
This is why debulking effect is not immediate and requires follow-up bronchoscopy in 7 to 10 days to clean up the necrotic tumor tissue. Cell death depends on the freezing time, thawing time, lowest temperature reached, number of freeze-thaw cycles, and water content of the tissue. Effective killing zone is 5 to 8 mm.10,11 Tissues with higher water content, such as skin, granulation tissue, mucous membrane, nerve, endothelium, tumor tissue are cryosensitive, whereas cartilage, connective tissue, fibrous tissue, fat, and nerve sheaths are cryoresistant.12
TECHNIQUES OF CRYOTHERAPY
Cryotherapy can be used in treating and diagnosing various lung diseases (Table 1).
Cryoprobe Technique for Treatment of Endobronchial Lesions (both benign and malignant lesions, such as granulation tissue and endobronchial tumors [carcinoma, carcinoid])
True endobronchial lesions and infiltrating lesions with luminal component can be treated with freeze-thaw method, cryodebridement (recanalization), or cryospray. This therapy should not be used in extrinsic lesions compressing the airway.
Freeze-thaw cryotherapy is used to debulk granulation tissue or benign/malignant endobronchial lesions. After the tip of the probe is pushed onto the lesion with full contact, three cycles of freezing (20 to 60 s) is delivered at same location with 5 to 6 mm distance between each application. Freezing cycles create approximately a 10 mm ice ball.13,14 In patients with critical airway narrowing, freeze-thaw method should not be performed considering the fact that cell death will take place in few days requiring actual debulking and/or removing the necrotic tissue in 1 to 2 weeks after the initial freezing procedure.
In contrast, cryodebridment or cryocanalization can provide faster debulking to establish airway patency by using the cryoprobe in the center of the tumor and airway with freezing up to 20 seconds and removing the tissue with the probe right after freezing. This method may result in bleeding and may require hemostatic therapies such as argon plasma coagulation (APC), diluted epinephrine irrigation, or compression with balloon catheters.
In 2012, the FDA approved a device to deliver spray cryotherapy for the destruction of unwanted tissue in the airway (TruFreeze system, CSA Medical Inc.). This system provides liquid nitrogen spray which flash freezes a 2 to 3 cm oval target area with depth of freeze up to 5 mm.15 Because liquid nitrogen droplets turn into nitrogen gas in the airways and potentially displaces the oxygen leading to barotrauma, the nitrogen gas should be evacuated from the airways by passive venting through the rigid bronchoscope or around and through the endobronchial tube with the cuff deflated and disconnected from the ventilator circuit.
Intraoperative Treatment of Parenchymal Tumor
Direct intrathoracic cryotherapy may be an alternative to those patients who were thought to be resectable but found to be unresectable during surgery.16,17
This approach requires precise localization, measurement, and tumor relation to major vessels. The cryoprobe is placed tangential or in contact at the cranial aspect of the tumor and freezing is continued until the iceball is large enough to cover the tumor and a 5 to 10 mm margin of normal lung tissue around it. Two cycles of freeze-thaw are recommended to prevent significant bleeding. Multiple cryoprobe applications may be needed for larger tumors. Necrotic tissue can then be mechanically removed.
Percutaneous Treatment of Parenchymal Tumors
Percutaneous cryosurgery can be performed under local or general anesthesia placing the cryoprobe directly into the targeted tumor under computed tomography guidance. The cryoprobe uses high-pressure argon and helium gas for freezing and thawing, on the basis of the Joule-Thompson principle. The procedure consists of 2 cycles of 5 minutes of freezing followed by slow thawing up to 20° C, then a third cycle of 10 minutes of freezing-thawing. Because air in the alveoli prevents conduction of low temperatures, repeating cycles of freezing-thawing cycles causes hemorrhage in the alveoli that leads to larger ice ball formation up to 2.5 to 3 cm when a 2 or 3 mm probe is used. Depending upon the tumor size, multiple probes can be placed to treat a larger tumor. Although 1 cryoprobe is usually inserted for tumors <2 cm, larger tumors may require more probes. Pneumothorax and hemopneumothorax are potential complications.18,19
Cryotherapy has advantages over other treatment modalities such as laser and APC; less expensive, no fire risk, can be used with high FiO2, very low risk for airway perforation as the cartilage and collagen tissue are cryoresistant.20
Transbronchial cryoprobe biopsy can be used for diagnosing lung rejection in transplant patients, lung cancer and interstitial lung diseases.
After the cryoprobe is advanced to the desired lobe approximately 10 to 20 mm away from the chest wall confirmed by fluoroscopic guidance, the probe is cooled for 4 seconds and then the bronchoscope and the probe are retracted simultaneously. The biopsy specimen is thawed with saline and kept in formalin.
Both foreign objects and secretions (mucous plugs or blood clots) can be removed. The visible endobronchial objects are frozen with the tip of the probe, either 1.9 or 2.4 mm, with full contact, and then the probe and foreign object are retracted together with the bronchoscope. Depending upon the size and shape of the object rigid bronchoscopy may be needed.
DIAGNOSING LUNG DISEASES
The diagnostic yield of transbronchial biopsies with standard forceps is often limited by crush artifact and smaller size. Moreover, transbronchial biopsies cannot frequently provide information about distribution of pathologic pattern throughout the lungs. Cryoprobe transbronchial biopsy offers potential diagnostic benefit over traditional transbronchial biopsies. Advantages of cryoprobe biopsies include larger specimen retrieval with higher number of alveolar units and higher quality of specimen with less crush artifact.21 The efficacy and safety of cryobiopsy had been evaluated for different lung diseases. Animal studies showed that flexible bronchoscopy with cryoprobe biopsy were a safe diagnostic technique.22
The current gold standard in evaluating the post transplant lung allograft is jaw-forceps transbronchial biopsies via flexible bronchoscopy. Samples obtained may lack quality because of crush artifact and limited sample size. Therefore, a minimum of 10 biopsies is recommended to optimize the diagnostic yield. This imposes a significant risk for the patient because the risk of bleeding and pneumothorax are increased with each biopsy attempt. Higher diagnostic yield, bigger sample size, and architectural preservation of tissue make cryobiopsy an attractive option for lung transplant patients. Recently, Yarmus et al23 studied the safety profile and diagnostic yield of cryobiopsy in lung transplant patients. In this pilot study, the use of cryobiopsy in patients after lung transplantation was safe and provided significantly larger specimen for pathologic evaluation. Specimen area and percent of open alveoli were significantly greater when compared with forceps biopsies (P<0.05). Although lung transplant patients have a higher risk of bleeding after transbronchial biopsies in general, the occurrence of bleeding after cryobiopsy was comparable with forceps biopsies. Similarly, Fruchter et al24 reported larger diameter of biopsy (10 mm2 vs. 2 mm2, P<0.05) and percentage of alveolated tissue (64% vs. 34%, P<0.05) when compared cryoprobe with forceps biopsy. Other advantages of cryobiopsy are that fluoroscopy time is greatly reduced. Larger sample size preserving small blood vessels and terminal bronchioles are essential to detect lung transplant allograft rejection. This is also imperative for the diagnosis of chronic allograft dysfunction and bronchiolitis obliterans. The procedure was shown to be safe when performed with conscious sedation and flexible bronchoscopy without the need of general anesthesia and rigid bronchoscopy.25
Interstitial Lung Disease
Transbronchial biopsy plays a minor role in the diagnosis of interstitial lung diseases (ILD). It is mainly used to rule out granulomatous disease or infection. Surgical lung biopsy is the gold standard for the diagnosis of ILD largely because it provides a much larger specimen with preserved tissue architecture. Unfortunately, many patients cannot undergo surgical lung biopsy because of advanced disease at presentation. Because transbronchial cryoprobe biopsy provides much larger biopsy specimen than conventional forceps biopsies, it is an attractive potential diagnostic alternative in patients with ILD. In a feasibility study, Babiak et al25 showed the safety of cryobiopsy in patients with ILD where only 2 of 41 patients developed pneumothorax. Although diagnostic yield of biopsy technique was not a primary goal of the study, they reported that cryobiopsy contributed a definitive diagnosis (39 of 41 patients, when adding information from history, noninvasive testing, and imaging). This is probably because of the larger tissue sample, 15.11 mm2 in cryoprobe versus 5.82 mm2 in forceps biopsies, respectively. Pajares and colleagues directly compared the diagnostic yield of conventional transbronchial biopsy and cryobiopsy in patients with diffuse interstitial lung disease. They reported that cryobiopsy has a significantly better yield in this particular group of patients without increase in complication rates.26 At present, there is an ongoing clinical trial comparing video-assisted thoracic surgery and cryobiopsy for the diagnosis of patients with ILD. The purpose of this study was to assess the diagnostic yield and the safety of cryobiopsy in comparison to surgical lung biopsy. Hopefully, results of this study will better define the role of cryobiopsy in the diagnosis of patients with ILD.
Another possible diagnostic application of cryobiopsy is the diagnosis of lung tumors. Aktas et al27 investigated the accuracy and efficiency of cryobiopsies in histopathologic diagnosis of endobronchial exophytic lesions. They reported that cryobiopsy has higher diagnostic yield without any increase in complications. Similarly, Hetzel et al,28 in a prospective randomized single-blinded multicenter trial, compared cryobiopsy with conventional forceps biopsy in diagnosis of lung cancer irrespective of cell type. They reported a higher diagnostic yield for cryobiopsy. This is of increasing importance in lung cancer because better quality of tissue obtained by cryobiopsy may facilitate identify molecular targets of adenocarcinoma. Larger sample obtained by cryobiopsy is particularly helpful for the diagnosis of small cell lung cancer where necrotic tissue can conceal typical cancer histology.
Schumann et al29 also found that cryobiopsy has a higher diagnostic yield in lung cancer with less or comparable bleeding rates than conventional forceps biopsy (Table 2).
TREATING LUNG DISEASES
Cryotherapy has been used in treating benign and malignant lung diseases.
Benign lesions of the tracheobronchial tree are relatively rare.30 Management of these lesions requires ruling out malignancy at presentation and treatment if they cause mechanical obstruction in the airways. Although parenchymal lesions require surgical resection, purely endobronchial lesions can be treated with one or combination of endoscopic modalities such as endoscopic curettage, electrocautery, Nd-YAG laser, or cryosurgery.
Endoluminal Lesions, Nontransplant Related
Moorjani et al31 published a 20-patient case series with various benign lesions including tracheobronchopathia osteochondroplastica (4), sarcoidosis (4), polyps (3), papilloma (2), nontransplant granulation tissue (2), amyloidosis (1), lipoma (1), leiomyoma (1), postintubation tracheal stenosis (1), and hemangioma (1). All patients described improvement in at least 1 of their symptoms (dyspnea, cough, stridor, hemoptysis, or chest pain). Spirometric indices improved in all patients. Complete removal of lesion was achieved in 15 (75%) patients, whereas remaining tissue was observed in 5 patients who required further treatment later on. None of the patients experienced major bleeding or airway perforation. Minimal bleeding was treated with topical application of epinephrine (1:1000). Other case reports described therapeutic use of cryotherapy for recurrent respiratory papillomatosis, endobronchial lipomas, and hamartoma.32–34
Lung Transplant-related Airway Complications
Incidence of airway complications after lung transplantation was described in 7% to 18% of patients with a related mortality of 2% to 4%.35,36 Bronchial stenosis is the most common airway complication incidence ranging from 1.6% to 32% and usually occurs secondary to necrosis, dehiscence healing, or infections.37 Although dilatation is the first intervention performed, its effect usually is not long lasting and other additional modalities may be needed including cryotherapy, electrocautery, laser, or brachytherapy in the management of bronchial stenosis.38 Benign hyperplastic endobronchial granulation tissue can cause significant airway obstruction in up to 20% patients, typically at the anastomotic site, within the few months of lung transplantation. Debridement is the modality of care with forceps resection, cryotherapy, or Nd-YAG laser.39,40
Lung cancer is the leading cause of cancer deaths worldwide.41 Nearly 180,000 patients are diagnosed with lung cancer in the United States annually and more than half of these patients are expected to have involvement of the central airways.42 This can be in the form of endobronchial disease with or without tumor extension into the endobronchial lumen or extrinsic compression, potentially leading to airway compromise. Cryosurgery has been used to treat patients with inoperable obstructive central bronchial tumor where it is shown to be effective in reopening the airway. Endobronchial tumor debulking can be achieved with cryoprobe (delayed effect with ablation or immediate effect with cryocanalization) and cryospray. Besides endobronchial use of cryotherapy, direct cryotherapy has also been used to treat inoperable patients during surgery. As advances are made in imaging guidance and improvement in cryotechnology, percutaneous form of cryosurgery has also become an option for treatment of lung cancer, in early and advanced stages.18
Overall, cryotherapy has been used in various patient populations ranging from advanced inoperable cases with palliative intent to early lung cancer patients with comorbidities who are not candidates for surgery.16,43–56
Percutaneous cryosurgery method is also used in conjunction with chemotherapy and radiation therapy in several studies showing cryosurgery as a safe and effective option, revealing favorable results in terms of improved median survival.49,57–60
CRYOTHERAPY FOR CENTRAL AIRWAY OBSTRUCTION
Cryoprobe can provide effective debulking of the endobronchial tumors. This has a delayed effect because of time needed for cell death and development of tissue necrosis. Therefore, this is not the preferred treatment modality for critical large airway narrowing. Cryotherapy has shown significant symptom relief with excellent safety profile in the right candidates. The only downside is the need of cleanup bronchoscopy in 1 to 2 weeks and repeated treatment for residual tumor43,49–52 (Table 3).
Cryotherapy can also be used in high-degree airway obstructions if immediate debulking is needed. This relies on removing the tumor tissue from the center of the airway to recanalize the air passage. This provides immediate improvement in symptoms and performance score. Because some bleeding is expected in the remaining tumor tissue after each pass of removal of tumor piece, a coagulation method, such as APC, might be needed53,54 (Table 4). Cryotherapy can be used in conjunction with other endoluminal debulking techniques, but there is no extensive experience or research exists.
Direct cryosurgery, if available, might be an option when the patient is deemed inoperable during VATS or thoracotomy.
Maiwand and colleagues used direct cryosurgery on 15 patients during exploratory thoracotomy. The intraoperative findings of no possibility of resection for tumor led to the decision not to perform lung resection, instead direct cryosurgery. There was increase in FEV1, FVC, as well as Karnofsky and WHO scores. Postoperatively, no complications were encountered related to the procedure. A measurable reduction in tumor size was recorded in the mass in 3 of the 15 patients.16
Percutaneous cryoablation of lung cancer under computed tomography guidance with local anesthesia has become an option in those who are not operable candidates because of comorbidities (Table 5). Largest case series published by Niu et al18 reported the results of 840 patients with non–small cell lung cancer stages IIA to IV. It is noted that tumor size initially increased after cryotherapy followed by shrinkage and cavitation in the tumor. Complete response was seen in 86 patients (14.4%), whereas 588 (70%) had a partial response. Tumor recurrence was noted in 47.2% with 28.3% of them at the cryoside. Survival benefit with cryotherapy was better than chemotherapy with or without radiation, overall survival ranged from 5 to 61 months (mean 23 mo). The same group published 64% 2-year survival in their non–small lung cancer stage IIIB-IV patients.19
Complication rates are found to be higher with this technique, such as pneumothorax (12% to 25.9%), pleural effusion, and hemothorax (16.2% and 22.5%, respectively).18,19
FOREIGN BODY REMOVAL
Foreign object (FO) aspiration is usually encountered in children and accounts around 500 to 2000 deaths annually in the United States.61–63 FO aspiration can be organic (mucous, blood, or food) or inorganic (dental work, pin). Depending on the location, nature, and the shape of the FO, different equipment is used to retract the FO, including forceps, Fogarty balloon catheter, baskets, magnets, or cryotherapy. When cryoprobe is placed in contact with a FO, the cryoprobe can be iced and adhered to the FO, making it feasible to retract with bronchoscopy.64 In children, rigid bronchoscopy offers good visualization and use of a much wider range of type and sizes of forceps. Flexible bronchoscopy has been reported to be as successful in removing most FO in adults.65 Food particles with high water content are easily removed with cryoprobe as are inorganic objects.66
LIMITATIONS AND COMPLICATIONS OF CRYOTHERAPY
Although cryotherapy is safe and less expensive than other endoluminal techniques and easy to use, it has limitations. From equipment stand point, some consoles have no timer and the duration of cryotherapy application is operator dependent; therefore, dosimetry will not be standard on each application. This may be problematic if the treatment is applied too long that may lead to higher rate of complications. Because effect of cryotherapy takes few days when freeze-thaw method is used for debulking purpose, multiple bronchoscopies may be needed to clean up necrotic tissues. This also limits the use of cryotherapy in cases with critical airway obstruction and also will increase the overall cost. When cryotherapy is used for cryodebridement (cryorecanalization), bleeding may occur and other modalities such as APC may be needed to control the bleeding.
Safety of cryotherapy has been shown when used for diagnostic or therapeutic purposes. Most commonly encountered complications of cryotherapy are bleeding, pneumothorax, airway obstruction with sloughed tissue leading to respiratory failure, pneumomediastinum, and gas embolism. Needles to say, airway tear is a potential complication when cryotherapy is used aggressively, especially in mixt airway malign obstructions. Cryospray technique requires passive venting during flow spray cryotherapy to avoid complications such as bradycardia, hypotension, and pneumothorax as discussed above.
As a new technology in diagnosing lung diseases, cryotechnology has great potential to be used in wide range of pulmonary diseases. Although there are already studies showing comparable results with forceps transbronchial biopsies in diagnosing rejection in transplant patients, it has also been used in ILD and lung cancer. The cases with lung disease and too sick to have surgical lung biopsy may benefit from cryobiopsies, owing to obtain larger biopsy specimens than forceps biopsy. Although most practitioners apply cryoprobe only for 4 seconds while obtaining lung biopsies, prolonged duration will provide larger tissue. This should be studied and the duration should be standardized in various clinical situations.
Although there are few studies showing additional benefit of cryotherapy when used in conjunction with chemo and radiation treatments, this area has not been extensively studied. Similarly, there is no extensive knowledge about utility of cryotherapy with other endoluminal technologies.
Future studies will answer all these questions.
Cryotherapy is a new and emerging technology that adds to the armamentarium of interventional pulmonologist and thoracic surgeons dealing with patients with complex diseases of the lung. Besides its therapeutic use in lung cancer involving central large airways or lung itself, cryotherapy now is used for diagnostic purposes in ILDs, lung cancer, or determination of lung rejection in transplant patients. Further studies will delineate the spectrum of cryotherapy in diagnosis of wide variety of lung conditions.
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