Chapter 10
Bronchoscopic cryotherapy and cryobiopsy
Rajesh Thomas1,2 and Martin J. Phillips1,2
1Dept of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia. 2School of Medicine, University of Western Australia, Perth, Australia.
Correspondence: Rajesh Thomas, School of Medicine, Harry Perkins Building, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia. E-mail: rajesh.thomas@health.wa.gov.au
Bronchoscopic cryotherapy is one of several complementary modalities that can be used for the management of malignant and benign endobronchial diseases. Cryotherapy can safely restore airway patency and improve symptoms in patients with central airways obstruction from exophytic tumours. It is also used in the treatment of granulation tissue and benign strictures, and to remove inhaled foreign bodies or impacted biological matter. Bronchoscopic cryobiopsy in endobronchial tumours and ILD improves diagnostic yield, and provides large amounts of well-preserved, high-quality tissue. However, the risk of severe bleeding following cryobiopsy is a major concern, and knowledge gaps remain about the ideal technique and patient selection. Future research must characterise the risks versus benefits of cryobiopsy compared with surgical lung biopsy and its role in the evaluation of diffuse parenchymal lung diseases. Research into novel applications of cryotherapy is underway and has the potential to transform the practice of interventional pulmonology.
Cite as: Thomas R, Phillips MJ. Bronchoscopic cryotherapy and cryobiopsy. In: Herth FJF, Shah PL, Gompelmann D, eds. Interventional Pulmonology (ERS Monograph). Sheffield, European Respiratory Society, 2017; pp. 141–161 [https://doi.org/10.1183/2312508X.10010517].
Cryotherapy is the use of extreme cold to freeze and so sample, damage or destroy human tissue. Bronchoscopic cryotherapy for thoracic diseases was initially used in the 1970s to treat inoperable endobronchial tumours. Since that time, applications have greatly expanded from being a bronchoscopic therapeutic debulking tool (by cryoablation) to include other forms of airway recanalisation treatments (e.g. cryorecanalisation and cryoextraction techniques) and diagnostic techniques (cryobiopsy).
Cryoapplications for thoracic diseases are known by various terms in the literature, including cryotherapy, cryoablation, cryorecanalisation, cryodebridement, cryocautery, cryosurgery, cryoextraction and cryobiopsy. The following terminology will be used in this chapter to describe the different cryotechniques. 1) Cryoablation: application of alternating freezing and thawing cycles to induce delayed cellular necrosis and tissue destruction. 2) Cryorecanalisation: debulking of an exophytic tumour by repeated cryoadhesive freezing and removal, leading to immediate re-establishment of airway patency. 3) Cryoextraction: removal by adhesive freezing of an inhaled foreign body, blood clot or impacted biological tissue (e.g. a mucus plug in the airway). 4) Cryobiopsy: sampling of bronchial, lung or pleural tissue by a cryoadhesion technique for histopathological evaluation.
Bronchoscopic cryotherapy is one of several modalities that can be used for the management of endobronchial conditions, both malignant and benign. Such therapies include laser photocoagulation, electrocautery, APC, mechanical debridement, airway stenting, PDT, radiotherapy (both brachytherapy and external beam) and chemotherapy. Each modality has its own properties and role to play, and many of these techniques and therapeutic procedures are discussed in more detail throughout this Monograph [1].
Here, we review the literature on bronchoscopic cryotherapy and cryobiopsy for thoracic diseases, and discuss their roles, principles, indications, techniques, outcomes and safety. Key gaps in knowledge, which may guide future research, are highlighted.
Literature search
MEDLINE, Excerpta Medica and the Cochrane Database of Systematic Reviews were interrogated using the following search terms: “cryotherapy”, “cryoablation”, “cryorecanalisation”, “cryodebridement”, “cryocautery”, “cryosurgery”, “cryoextraction”, and “cryobiopsy”; and “bronchoscopy”, “thoracoscopy”, “endobronchial tumour”, “lung cancer”, “endobronchial biopsy”, “transbronchial biopsy”, “lung biopsy” and “pleural biopsy”. References and their citation lists were scrutinised.
History
In 1850, James Arnott invented a device using salt and crushed ice solution to treat breast and skin cancer by freezing (−24°C) [2, 3]. Improvements in cryotechnology using liquefied gas over the next century led to further advances in medical cryoapplications, including cryotherapy [4–6]. Cryotherapy was initially used in the treatment of skin cancers; later, closed-tip and specially shaped applicators called cryoprobes were employed for the delivery of cryotherapy to cancers in other anatomical areas [7, 8].
A rigid cryoprobe applicator for endobronchial cryotherapy was successfully used in the 1960s [8]. The Mayo group pioneered the bronchoscopic cryoablation technique to treat bronchogenic tumours [9–15]. Early work in animals showed that the cryoablation process caused a localised and reproducible mucosal ulceration that evolved within 6 h and healed by 2 weeks [13, 16]. Cryonecrosis and subsequent repair of the frozen tracheal cartilage lagged the mucosal changes, but also normalised by 4 weeks. In 1975, SANDERSON et al. [15] reported the first case of bronchoscopic cryotherapy by cryoablation in a patient with endobronchial cancer. During the following decades, many American and European centres adopted this method of endobronchial cryotherapy to debulk tumours in the central airways and relieve endobronchial strictures, and demonstrated its effectiveness and safety [17–22].
The introduction of a nonrigid cryoprobe with interchangeable tips allowed cryotherapy to be extended to tumours in the upper lobe bronchi [20]. The subsequent development of a fully flexible cryoprobe that could be used along with a flexible bronchoscope provided more versatility [23]. This, combined with improvements in the tensile strength and freezing power of the flexible cryoprobe, enabled a more rapid debulking of endobronchial tumours by the cryorecanalisation method [24–26] and transformed thoracic cryopractice. More recently, spray cryotherapy (SCT), a technique that utilises non-contact-mode flash-freeze from vapourised liquid nitrogen, has been approved for bronchoscopic treatment of airways pathology [27–30].
Today, bronchoscopic cryotherapy is supported by major thoracic societies as an accepted treatment modality for inoperable airway malignancy [31, 32].
Cryobiology
Contact cryotherapy with a cryoprobe acts by cryoablation, a slow-freeze process that causes cell necrosis and tissue destruction through immediate and delayed effects [33, 34]. Immediate intracellular and extracellular ice crystallisation damages vital intracellular organelles such as mitochondria and endoplasmic reticulum, while efflux of intracellular fluid causes cellular dehydration and shrinkage, resulting in direct cell injury [7]. Delayed effects result from vasoconstriction, endothelial injury and microvascular thrombosis, causing tissue ischaemia that leads to selective cellular necrosis and cell death [33]. This ischaemic effect also extends beyond the immediate area of probe contact to cause surrounding tissue infarction.
SCT acts by a flash-freeze mechanism whereby liquid nitrogen applied directly onto the tissue vapourises (−196°C), causing intracellular ice formation and cell death. This method may have an advantage in promoting tissue regeneration as the extracellular matrix is preserved during the process [27, 35].
Sensitivity to cryotherapy is mainly determined by tissue water content and vascularity. Highly vascular tissues such as tumour, granulation tissue, mucous membranes and endothelium are very cryosensitive; fat, collagen, connective tissue and cartilage are cryoresistant and less susceptible to the cryoadhesive effect [33, 36, 37]. The differential effects of cryotherapy on different layers of the tracheobronchial tissue may allow mucosal healing without formation of strictures and bronchial cartilage or wall damage.
The extent of tissue damage is greater with more rapid freezing and slower thawing, a higher number and duration of freeze–thaw cycles, a lower applied temperature, a larger probe size, and a larger tissue contact area with the probe [33, 38–42]. A rapid fall in temperature to below −40°C results in >90% cell destruction [12, 43].
Equipment
Current bronchoscopic cryotechniques utilise the Joule–Thomson principle, in which rapid freezing is caused by the sudden expansion of certain gases, such as nitrous oxide (−89.5°C) and carbon dioxide (−78.5°C), moving from a high-pressure to a low-pressure region. The original cryotherapy techniques used liquid nitrogen (−196°C) based on its property of having an extremely low boiling point.
The cryoequipment is simple to set up, and consists of a cylinder containing a freezing gas (cryogen) stored under high pressure, a console (cryomachine) that controls the flow of cryogen and a catheter with a cryoprobe at one end to freeze target tissue by direct contact. The bronchoscopist uses a foot pedal to activate and regulate the flow of the cryogen through the catheter from the cylinder to the cryoprobe. The cryogen rapidly freezes the tip of the cryoprobe as it exits a higher pressure region within the catheter to a lower pressure region outside the probe (figure 1). The theoretical lowest temperature for the gas is achieved only inside the probe immediately as it exits the catheter; the actual freezing temperature achieved on the outside of the probe is usually slightly higher. Spontaneous defrosting occurs once the flow of the cryogen is ceased following deactivation.
Figure 1. Flexible cryocatheter with an ice ball formed on the tip of the probe after freezing.
Endobronchial cryoprobes are of different types (rigid, semirigid and flexible), and have probe tips of various shapes (straight and angled) and diameters (1.1–2.4 mm flexible and 2.4–5.5 mm rigid probes). The larger rigid cryoprobe can treat more tissue in a shorter period as it has an additional mechanism for active thawing that allows a shorter freeze–thaw cycle. Thawing is spontaneous and, therefore, slower with a flexible probe; however, the slower thawing process has the advantage of causing more tissue necrosis.
Rigid cryoprobes can only be used with a rigid bronchoscope. A rigid probe with straight forceps is used to treat lesions in the central airways and lower lobes, while forceps with an angled tip are needed for lesions in the upper lobe bronchi [17]. A flexible cryoprobe is easier to use as it can be inserted through the working channel of a flexible bronchoscope; a flexible cryoprobe can also access the distal bronchi and peripheral lung parenchyma, in addition to the central airways [23].
General considerations
Debulking an endobronchial tumour to relieve central airways obstruction is primarily a palliative procedure, and is performed in patients with inoperable disease to improve distressing or life-threatening symptoms and quality of life. An interventional pulmonologist has many bronchoscopic modalities to choose from, including cryotherapy, to achieve optimal palliation. Cryotherapy can be used alone or, on occasion, together with other methods such as laser, electrocautery, APC, mechanical debridement, PDT and brachytherapy. These are complementary techniques that act through different effects on tissue so that often a multimodality approach may be required to optimise patient outcomes [1].
The optimal choice of bronchoscopic treatment depends on the availability of treatment equipment, expertise of the bronchoscopy team, site (central versus peripheral) and type (intraluminal versus extraluminal) of airways obstruction, extent of disease, and performance status of the patient. A patient with a short endoluminal lesion and patent distal airway is appropriate for bronchoscopic tumour debulking. In the case of critical airway obstruction, urgent recanalisation is necessary and best achieved by cryorecanalisation, laser, APC or mechanical debridement. Cryoablation, brachytherapy and PDT are unsuitable because their effects are delayed.
As with any bronchoscopic intervention, patient selection and assessment for cryotherapy are crucial, and should be individualised. This involves a complete clinical examination, assessment of performance status, CT evaluation, pulmonary function testing, evaluation of fitness for anaesthesia and assessment of bleeding risk. Anticoagulant and/or antiplatelet drugs, particularly clopidogrel, are ceased preoperatively.
Cryoprocedures can be performed under general anaesthesia or intravenous sedation. High-risk procedures such as bronchoscopic cryorecanalisation and cryobiopsy are best performed under general anaesthesia with a rigid bronchoscope or endotracheal tube in place as this allows better ventilation and adequate control of the airway in case of complications, particularly severe bleeding. A combined approach using a flexible bronchoscope introduced through a rigid bronchoscope or endotracheal tube during cryoadhesive procedures provides both the flexibility to reach less accessible regions in the tracheobronchial tree and the ability to rapidly withdraw the flexible bronchoscope, cryoprobe and attached frozen tissue, and re-introduce the scope.
Therapeutic cryoapplications
Cryotherapy: cryoablation and cryorecanalisation
Cryoablation
Bronchoscopic cryoablation was the original cryotherapy method used to debulk central airway tumours. Cryoablation causes freeze injury to effect cellular necrosis, tissue devitalisation and tumour destruction.
Technique
The endobronchial tumour is exposed to multiple freeze–thaw cycles during the bronchoscopic cryoablation procedure. The distal tip of the flexible bronchoscope is held just above the target area when using a flexible cryoprobe; the tip of the probe is pushed 5–10 mm beyond the bronchoscope to touch the lesion perpendicularly, tangentially or within and then activated under direct visualisation. Activation while the probe tip is still inside the working channel of, or too close to, the bronchoscope can cause damage to the scope and cryoprobe from ice crystal formation.
Each freeze–thaw cycle lasts for 1–3 min and is repeated up to three times at each region depending on the size and depth of the lesion [17, 18, 20, 23, 44]; this process is then performed sequentially in an adjoining region until the entire tumour is treated. Freezing variably damages the surrounding tissue depending on the size and freezing power of the probe, the probe–tissue contact area and the tissue type [37]. Additional treatments, spaced 2–4 weeks apart, may be necessary.
Blood and slough are often seen following cryoablation of large necrotic tumours. This is removed either in between the cryoapplications by cryoextraction with the cryoprobe and/or with forceps, or continuously using a suction catheter deployed through a rigid bronchoscope. The remaining frozen tissue undergoes delayed necrosis, and is sloughed off and expectorated over the following days. A clean-up bronchoscopy may be necessary within 5–14 days to debride and remove devitalised tissue and airway secretions [23].
SCT also has similar disadvantages of delayed treatment response and the need for follow-up bronchoscopy [28, 35, 45]; it is therefore not recommended for cryoablation of tumours causing critical airway obstruction. Of concern, the early studies of SCT also showed high rates of severe complications related to barotrauma and hypoxaemia [28]. Further research to refine the technique and establish the safety and efficacy of SCT is needed.
Cryorecanalisation
Cryorecanalisation is a more recent bronchoscopic technique. It utilises the power of cryoadherence, instead of repeated freeze–thaw injury, to forcefully shear off tissue such as tumour, adherent on the frozen tip of the cryoprobe. During the cryorecanalisation process, the endobronchial tumour is debulked piecemeal by repeating the process of cryoadherence and tissue removal many times. This allows a more rapid clearance of an obstructed airway in a single bronchoscopic session and is a major advantage compared with the slower cryoablation method [24, 26].
Technique
HETZEL et al. [24] first described the cryorecanalisation technique using a flexible catheter cryoprobe. The tip of the cryoprobe is guided through the working channel of the flexible bronchoscope, placed tangential, perpendicular or within the tumour and frozen for up to 20 s. The depth and extent of the ice front can be controlled under direct vision to ensure that only the diseased area, not healthy tissue, is frozen. After adequate freezing, both the cryoprobe and bronchoscope are firmly pulled back together to tear the adhered tissue away from the bronchial wall. The tumour breaks off easily from the bronchial wall when traction is applied as the ice formation is inhomogeneous in the transition area between the tumour and normal bronchial wall.
As the frozen tissue attached to the probe is larger than the working channel of the flexible bronchoscope, the scope, cryoprobe and adhered tumour are removed en bloc; the tissue is then removed by immersion and thawing in saline. This process is repeated multiple times to rapidly remove tumour pieces and recanalise the airway (figure 2).
Figure 2. a) CT (axial view) of thorax showing a tumour (arrow) arising from the right upper lobe and completely obstructing the right main bronchus. b) Bronchoscopic view of the tumour completely obstructing the right main bronchus. c) Piecemeal removal of tumour adherent to the cryoprobe. d) Re-establishment of patency of the right main bronchus following cryorecanalisation procedure. e) Pre- and f) post-cryorecanalisation chest radiographs showing re-expansion of collapsed right middle and lower lobes. The right upper lobe tumour and collapse persist.
Outcomes
Cumulative data show that complete or partial restoration of airway patency occurs in 59–90% of cases after bronchoscopic cryoablation [17, 20, 21, 23] and in >80% of cases after cryorecanalisation [24–26]. Cryotherapy improved dyspnoea (37–86% of cases), haemoptysis (67–100%), performance scale (63%), oxygenation (66–71%), radiology (59%) and pulmonary function (in 28% of cases with mean improvements in FEV1 and forced vital capacity of 0.12 and 0.2 L, respectively) [17, 18, 20, 21, 23, 44]. Further interpretation of this data is not possible given that most reports were of uncontrolled cohort studies with variable outcome measures, definitions of success and heterogeneous populations.
Treatment success of bronchoscopic cryotherapy is determined by the location and type of the tumour, and the type and number of cryotherapy procedures. Cryotherapy is very effective in the treatment of endobronchial exophytic tumours, although cryotherapy may need to be repeated in the case of large tumours. A higher success rate is seen with cryorecanalisation and repeated treatments [46]. Submucosal or extrinsic tumours are best treated by airway dilatation and/or placement of an airway stent [47, 48].
Complications
The safety profile of cryoablation treatment is comparable to, or better than, other interventional bronchoscopic modalities; however, this has to be balanced against the relatively limited and delayed therapeutic effects. Most complications are minor (e.g. airway oedema, bronchospasm and fever) that could be managed with conservative measures [49]. However, mucosal oedema, necrotic debris, blood and secretions following cryotherapy can worsen critical airway obstruction and cause respiratory distress [25]. This is not unique to cryoablation and could occur regardless of the bronchoscopic intervention chosen as these procedures are inherently high risk due to the nature of advanced cancer, extent of airway obstruction and impairment of cardiopulmonary reserve.
Bleeding is the major complication associated with cryorecanalisation [24–26]. Mild bleeding (requiring cold saline or topical epinephrine) and moderate bleeding (requiring APC or a bronchial blocker) following recanalisation were seen in 4% and 8% cases, respectively, in one series (n=225) [26]. Severe bleeding causing haemodynamic instability did not occur in this series; however, it is advisable to avoid cryorecanalisation in highly vascular tumours. Prophylactically devitalising vascular tumours using APC or electrocautery further reduces the risk of bleeding [25].
Cryotherapy versus other bronchoscopic therapeutic interventions
Bronchoscopic cryotherapy has many advantages and few limitations compared with common bronchoscopic modalities, yet remains underutilised [50]. It is easy to learn and perform; international guidelines recommend 10 supervised procedures is sufficient to establish competency [51]. The procedure is well tolerated by the patient and most patients can be discharged home on the same day.
The initial establishment costs and recurring expenses for cryotherapy are significantly lower than other modalities. The cost of consumables is minimised as the cryoprobe catheter can be reused after sterilisation. The main operational expense is for the cryogen that needs replacement depending on usage. The cryotherapy equipment is portable, and can be set up quickly and easily. In comparison, treatment with laser therapy is expensive due to the high initial cost of a laser unit, and the recurring cost for maintenance of the laser unit and the disposable catheters. Optical protection and specialised safety training for the bronchoscopy team are also necessary when using laser therapy.
Bronchoscopic cryotherapy also has safety advantages. The risk of cryonecrosis and accidental airway injury or bronchial wall perforation are low as bronchial cartilage and fibrous tissue are cryoresistant. Unlike with other bronchoscopic interventions, with cryotherapy there is little risk of collateral damage to covered metallic stents, radiation exposure, electrical injury or endoluminal fire when using high-flow oxygen.
Cryotherapy in early superficial bronchogenic carcinoma
There is no consensus on the ideal treatment method of early superficial bronchogenic carcinoma (ESBC). Limited data exist regarding surgical resection and bronchoscopic methods, including cryotherapy, laser therapy, electrocautery and PDT. Results from one cryoablation study involving 35 patients with 41 ESBC lesions showed complete response lasting >1 year in 91% of treated patients and up to 50% survival at 4 years [52]. This is comparable to the results of PDT without the severe or prolonged cutaneous photosensitisation associated with PDT [53–55]. Future studies comparing cryotherapy with surgery and other bronchoscopic treatments for ESBC are needed.
Cryotherapy in benign airway disease
Bronchoscopic cryotherapy is an excellent treatment modality for removal of cryosensitive benign endobronchial tumours such as hamartoma (figure 3) [56]. Endobronchial lipomas, despite the relative cryoresistance of fat, are also treatable by cryotherapy [57, 58]. BERTOLETTI et al. [56] performed bronchoscopic excision of carcinoid tumours and cryoablation of the implantation base in 18 patients. Tumour recurrence was seen in one patient only after 7 years; none developed bronchial stenosis or long-term complications.
