In endobronchial tumor debulking, the choice of cryotherapy has an evidence level 3 and grade of recommendation D [16]: the same level of recommendation is for electrocautery, argon plasma coagulation, Nd:YAG laser, and stent application, even if each procedure has its safety profile and own indications.

The systematic review by Lee et al. [18] investigated efficacy and safety of endobronchial cryotherapy in lung and bronchial tumor. A total amount of 16 studies were included in the analysis. Patients’ population was very diverse, including patients with primary lung cancer, metastatic cancer, benign tumors, and early superficial lung cancer; moreover, due to the variability of methods and the lack of procedure standardization, statistics analyses were not done. Cryotherapy was demonstrated to be effective in approximately 80% of cases and was effective in improving quality of life, symptoms, dyspnea, and pulmonary function especially in inoperable cases.

Maiwand et al. reported 75 cases of advanced tracheobronchial carcinoma (45 squamocellular carcinoma, 7 adenocarcinoma, 18 undifferentiated large cell carcinoma, 5 undifferentiated small cell carcinoma), treated with cryotherapy to relieve symptoms [9]. The majority of patients experienced an improvement of symptoms like stridor, dyspnea, and hemoptysis; 12 patients did not improve, 6 patients worsened, and 1 patient died from nonsurgical cause. Similar results were reported few years later by the same author: in a prospective cohort of 153 consecutive patients, cryotherapy provides effective and rapid control of symptoms caused by tracheobronchial carcinoma and an improved quality of life, with a median survival time of 12.9 months [31]. In this study, a rigid bronchoscope was used except for peripheral smaller tumors that were treated with a flexible bronchoscope.

In an Italian case series, Marasso et al. [33] investigated the therapeutic yield of rigid cryoprobes in 234 patients with malignant and nonmalignant stenosis: 183 patients with malignant tumors (mainly squamocellular carcinoma), 44 nonmalignant stenosis (4 adenoacanthomas, 6 polyps, 16 tracheal granulomas, 12 post-tubercolar heals, 6 leiomyomas and fibroleiomyomas), 4 bronchial carcinoid, and 3 bronchial cylindroma. In patients with malignancy, an improvement of lung atelectasis, hemoptysis, dyspnea, hypoxemia, and sepsis was obtained in 170 cases; in nonmalignant diseases, cryotherapy was also effective, but more settings were necessary to complete the treatment. This study underlined efficacy and safety of cryotherapy compared to other modalities like Nd:YAG laser, limiting its use in nonlife-threatening airway stenosis due to its delayed effect.

Cryotherapy was found to be safe and effective also in a report of 476 consecutive patients with obstructive tracheobronchial tumors [34]: an improvement in hemoptysis, cough, dyspnea, and chest pain was reported and also respiratory function and performance status improved. Survival analysis suggested a possible survival advantage over alternative palliative techniques. Maiwand and Asimakoupoulos [15] reviewed 521 consecutive patients with malignant endobronchial obstruction, not suitable for surgery due to the advanced stage of the disease or the poor clinical condition, which underwent endobronchial cryotherapy for palliation. Rigid probes were used in the trachea and in the main bronchi, and flexible probes were used in peripherally located tumor. There was a symptom improvement in 86% of patients, with a significant improvement in hemoptysis, cough, dyspnea, and chest pain in 76.4%, 69%, 59.25%, and 42.6% of symptomatic patients, respectively, and there was also a significant improvement in patient’s performance status in 63% of cases.

Asimakopoulos et al. [17] investigated the difference in efficacy of cryotherapy in one or two sessions. They reported the data of 329 patients that underwent at least two sessions of endobronchial cryotherapy (group A, n = 172) or one session of cryotherapy (group B, n = 157) from malignant (primary or metastatic) obstructive lung carcinoma. The most common histologic type of tumor was squamous, followed by adenocarcinoma, small cell carcinoma, and other tumors mainly metastatic. Most of the patients received palliative radiotherapy or chemotherapy, but those treatments were significantly lower in group B. Few patients underwent lung resection, 12 in group A and 8 in group B. About dyspnea, it was improved in both groups: in group A 50.5% of patients improved by at least one NYHA class; less degree of improvement was seen in group B. Similar results in both groups were reported about cough and hemoptysis. About lung function, there was a significant increase in group A in terms of PEF and FVC; the improvement of FEV1 was not significant. An improvement of Karnofsky score was seen in both groups. The mean survival was 15 months in group A and 8.3 months in group B. Patients who had radiotherapy showed longer survival. No particular tumor characteristic was associated with reduction of symptoms. Thus, on the whole, in this study, it was demonstrated that cryotherapy results in symptom relief, respiratory function, and in an improved performance status.

About cryoextraction, Hetzel et al. [3] described a cohort of 60 patients with high-grade airway stenosis from exophytic tumor (51 bronchogenic carcinoma, 4 metastases, 1 carcinoid, 3 granulation tissue and 1 malignant lymphoma). The target tissue was frozen at the tip of the probe and subsequently pooled away with the flexible bronchoscope. The treatment was successful in the 61% of cases, partially successful in the 22% and unsuccessful in the remaining 17% and 14% exhibited local recurrence. About complications, no deaths were recorded, 54 patients had bleeding that was self-limited, and 6 had more intense bleeding (100–300 mL) that was controlled with suction and argon plasma coagulation. In no cases was it necessary to switch to the use of a rigid bronchoscope. More recently, Schumann et al. [35] reported 225 patients with bronchoscopic cryo-recanalization with a flexible cryoprobe. A therapeutic success was achieved in 205 (91.1%) patients. The flexible cryoprobe by means of a flexible scope was used with all patients, and only in 31 cases a rigid bronchoscope was also used. Additional interventional techniques used were endobronchial stents and argon plasma coagulation. Bleeding was the most frequent complication and was mild in 9 patients (treated with ice-cold NaCl or epinephrine solution) and moderate in 18 patients (treated with argon plasma coagulation or bronchus blocker), while severe bleeding never occurred. Finally, Yilmaz and coll. reported similar results [36]: 40 patients with bronchial (primary or metastatic) malignancy were retrospectively included. A successful cryo-recanalization was achieved in 72.5% of patients; authors commented that the success was mainly related to the presence of the distal involvement and the older age of obstruction. Recurrences were observed in 17.2%, with a mean survival of 11 ± 12.7 months. Moderate bleeding occurred in ten patients, which was stopped with an argon plasma coagulator.

For early stage lung cancer, according to international guidelines [16], the choice of cryotherapy has an evidence level 3 and grade of recommendation D. Only few studies investigated the role of cryotherapy in early stage lung cancer. Deygas and coll. [37] described 35 patients with early superficial bronchogenic carcinoma treated with cryotherapy through a rigid bronchoscope. A therapeutic success was achieved in 91% of cases, local recurrences were observed in ten patients within 4 years, and no complications were observed.

No guidelines state a level of recommendation for metastatic endobronchial tumor. Few report described this application: [20, 25] reported the first use of cryotherapy in 35 patients with endobronchial metastases from extrapulmonary tumor. The 85% of patients improved their symptoms; in over half of the patients, endoluminal patency improved by ≥50% and survival ranged is from 10 days to 4 years and 8 months, with a median survival of 34 weeks. One-year survival was 37.5%. No complications were observed.

Lipomas : A retrospective multicenter study [26] reviewed the role of bronchoscopic techniques in the management of endobronchial lipomas. Out of 38 patients, 29 underwent laser therapy and mechanical debulking, cryotherapy and mechanical debulking in 7 patients, and mechanical debulking alone in 2 cases.

Hamartoma : Sarioglu et al. [27] reported a case of a man with a polypoid mass arising from the posterior wall of the anterior segment of the right lower lobe. The histopathologic diagnosis was lipomatous hamartoma, and it was resected with an electrosurgical snare, and subsequently cryotherapy was applied to residual lesion on the surface of the bronchus. Ucar [38] reported a case of hamartoma first cauterized using snare electrocautery probe and then removed with cryoextraction. Two other similar cases were reported by Sim et al. [39] using flexible bronchoscopy without complications.

Schwannoma : Le Rouzic et al. [28] reported a case of a patient with a tracheal mass at the CT scan; bronchoscopy revealed an endobronchial multi-lobular tumor with a moderate degree of vascularization. The patient underwent complete resection with a rigid bronchoscope followed by cryotherapy. No relapse was seen during the follow-up period.

Tracheobronchial carcinoid tumors : Dalar et al. [29] investigated the role of endobronchial treatment in patients with tracheobronchial carcinoid tumors. Twenty-nine patients with carcinoid tumor underwent endobronchial endoscopic treatment with diode laser or argon plasma coagulation. Cryotherapy was applied consecutively in patients for whom there were good bronchoscopic visualization of the distal and basal tumor margins and no evidence of bronchial wall involvement. There was no tumor-related death and no recurrence during the following 49 months. There was no difference for survival or recurrence between the surgical and the endobronchial treatment group of patients. Bertoletti et al. [40] studied safety and efficacy of cryotherapy via rigid bronchoscope for the treatment of isolated endoluminal typical carcinoid tumors. Eighteen patients were analyzed: all underwent a complete removal of the tumor and received cryotherapy on the implantation base. Only one patient had a recurrence after 7 years. Thus, cryotherapy was found to be safe and effective in adjunct to endobronchial mechanical resection. Finally, a recent case report by Chawla et al. [41] reported a case of carcinoid tumor successfully biopsied and treated with cryo-recanalization.

Fruchter et al. [42] investigated the cryo-adherence of various commonly aspirated objects. Organic objects like chicken and fish bones were adherent to cryoprobe, and inorganic objects like safety pin and paper clip were not retrievable by cryo-adhesion. Conversely, several inorganic objects like dental cup despite their low water content were cryo-adhesive. Authors proposed to test the cryo-adherence of the aspirated body before performing the procedure on the patient, if the nature of the aspirated body is not known.

To our knowledge, Sriratanaviriyakul and coworkers [32] described one of the largest case series. They reviewed 38 cases of patients with nonneoplastic tracheobronchial obstruction: the cryoprobe successfully reestablished airway patency in 32 of cases (84%), 24 blood clots, 4 mucous plugs, 2 foreign bodies, and 2 plastic bronchitis. In 68% the procedure resulted in an improvement in oxygenation or ventilation. No complications related to the procedure occurred, only one related to sedation. Lee et al. [31] described a case of a 66-year-old woman admitted for acute respiratory failure due to an obstruction of the left main bronchus from large blood clots. Flexible bronchoscopy failed to remove the clots, and they were removed using bronchoscopic cryotherapy at bedside in intensive care unit. Grosu et al. [34] reported a case of critical airway obstruction due to pseudomembranous Aspergillus tracheitis: cryotherapy removed successfully a 4 cm piece of tissue and the airway patency was restored. A successful cryoextraction of a chewing gum was reported by Rubio et al. [31]. Maiwand and coworkers [33] described a series of 16 patients with airway complications arising from granulation stenosis after heart-lung transplantation: cryotherapy was an effective treatment for excessive granulation tissue and reduced the need for endobronchial stenting and limited recurrences.