PD-1/PD-L1-negative tracheal mucoepidermoid carcinoma: A case report and systematic review of the literature

Background: Tracheal mucoepidermoid carcinoma is a rare form of non-small cell lung carcinoma and is dened as a tumor characterized by a combination of squamous, mucus-secreting, and intermediate cell types. This carcinoma is usually located in the lobar or segmental bronchus. Currently, surgery is the preferred treatment for this disease, which includes pneumonectomy, lobectomy, and sleeve lobectomy. Case presentation: A 50-year-old Chinese male presented with cough, shortness of breath and hemoptysis, and the effect of antibiotic therapy was not good. Subsequently, the airway occupied lesion was found by chest CT, and he was transferred to our hospital for surgical resection. Histologically, the tumor contained squamous epidermal cells, mucoepidermoid cells and intermediate cells. Immunohistochemistrically, the tumor cells were positive for p63, CK5/6, CK7 and Ki67. However, the tumor is generally negative for TTF-1 and neuroendocrine markers. The patient had no recurrence 15 months after the surgery. Conclusions: We report a rare case of mucoepidermoid carcinoma in the distal trachea in which the surgery was dicult and could not be performed like a traditional pulmonary resection. We rst provide a comprehensive description of airway management and anesthesia intubation. After surgery, we reviewed the literature and found that PD-1/PD-L1 detection had never been reported in tracheal mucoepidermoid carcinoma. Therefore, we studied the PD-1/PD-L1 pathway in this patient, and the results were negative, which may indicate that potential adjuvant therapy with immune checkpoint inhibitors (ICIs) is not useful in this case.

Immunohistochemistrically, the tumor cells were positive for p63, CK5/6, CK7 and Ki67. However, the tumor is generally negative for TTF-1 and neuroendocrine markers. The patient had no recurrence 15 months after the surgery.
Conclusions: We report a rare case of mucoepidermoid carcinoma in the distal trachea in which the surgery was di cult and could not be performed like a traditional pulmonary resection. We rst provide a comprehensive description of airway management and anesthesia intubation. After surgery, we reviewed the literature and found that PD-1/PD-L1 detection had never been reported in tracheal mucoepidermoid carcinoma. Therefore, we studied the PD-1/PD-L1 pathway in this patient, and the results were negative, which may indicate that potential adjuvant therapy with immune checkpoint inhibitors (ICIs) is not useful in this case.

Background
As a malignant neoplasm, the WHO named mucoepidermoid carcinoma (MEC) in 1990, and it was rst described as a separate pathological entity by Stewart in 1945 [1,2] . MEC accounts for <10% of all tumors of the salivary glands and mainly occurs in the parotid glands and small salivary glands. MEC originating from the trachea and bronchus is very rare; it accounts for 0.1-0.2% of primary lung tumors and is more prevalent in females (approximately 1.5 times) than in males. The onset age of tracheal MEC is relatively young, with the median age at presentation being approximately 40 years old [1] . The clinical symptoms are mostly atypical and mainly manifested as cough, hemoptysis, pneumonia, wheezing, fever, chest pain and other symptoms and signs; MEC is easily misdiagnosed as endobronchial tuberculosis, bronchitis or asthma [1,3] . Currently, surgery is the preferred treatment for this disease, but the choice of follow-up treatment is still uncertain. Immune checkpoint inhibitors against programmed death 1/programmed death ligand 1 (PD-1/PD-L1) have revolutionized the treatment of several solid tumors, and PD-L1 was reported to predict the response to immunotherapy [4,5] ; however, no studies have reported the expression of PD-1/PD-L1 in MECs. In this report, we describe the diagnostic, anesthetic, and surgical management of a MEC patient with negative PD-1/PD-L1 expression in the distal trachea.

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Clinical History A 50-year-old Chinese male complained of cough, shortness of breath and hemoptysis for 10 days. The situation did not improve with antibiotic therapy at a local hospital. He underwent chest computed tomography (CT), showing a polypoid tumor just above the main carina, and was transferred to our hospital. The patient was a smoker of 30 years, with an average of 20 cigarettes a day. No family history of malignancy was found. Physical examination demonstrated obvious retractions of the suprasternal, supraclavicular and intercostal regions.

Test results
Tumor markers were all normal, lung function showed ow limitation, and attening was noted in both the inspiratory and expiratory limbs of the ow-volume loop ( Table 1 and Figure 1A). Chest-enhanced CT found tracheal obstruction by a lobulated heterogeneous enhancing soft tissue measuring 2.2 cm, with suspected breakthrough of the airway wall, and no obvious enlarged lymph nodes in the mediastinum (

Operation and Pathological Examination Results
On December 19, 2019, the patient was referred for surgical management and underwent right posterolateral thoracotomy resection. Airway management was relatively di cult, and endotracheal intubation (via the mouth) was performed below the level of the lesion under general anesthesia. The trachea was incised at the lower edge of the tumor after careful separation, the endotracheal tube was withdrawn above the lesion and replaced by an auxiliary tube inserted into the distal left bronchus of the lesion to maintain adequate ventilation, the tumor segment trachea was resected along the upper and lower edges, and a frozen section veri ed that the tracheal margins were free of the tumor. End-to-end anastomosis was performed on the posterior wall of the trachea, the auxiliary tube was withdrawn, and the anastomosis on the anterior wall was completed without di culty, as shown in (+), SY (-), NapsinA (-), S100 (-), Ki67 (5%+), Calponin (-), CK5/6 (+), CK7 (small amount +), and PAS (-) 7-9: CK (-). The PD-1 and PD-L1 tests were negative (Figure 7). A diagnosis of primary tracheal MEC was nally determined, and no mediastinal lymph node involvement was observed.

Post-Operative follow-up
Postoperative recovery was satisfactory, and the outcome and surgical e cacy were investigated after 15 months of follow-up. Six months after surgery, activity endurance and pulmonary function (Table 1 and Figure 1B) were signi cantly improved, and no discomfort was reported. Chest CT ( Figure 2E, 2F) and bronchoscopy ( Figure 3C) indicated that the trachea was unobstructed and that there was no tumor growth. The patient subsequently returned to a local hospital due to poorly differentiated MEC for radiotherapy from July to September 2020. At the last telephone follow-up in March 2021, the patient was well without any signs or symptoms of recurrence.

Discussion And Conclusions
The incidence of tracheal MEC is low. While still controversial, MEC is generally believed to originate from the ductal epithelium of the submucosal glands of the bronchus [6] . Because the tumor mostly occurs in the lobar or segmental bronchi and especially in the peripheral lungs [7] , the early stage is asymptomatic, and a small number of patients were noted only during routine health examinations. As the tumor grows and blocks the bronchial lumen, the patient presents with clinical symptoms of airway obstruction, such as cough, sputum coughing and progressive shortness of breath, which are easily misdiagnosed as endobronchial tuberculosis, bronchitis or asthma [1,3,8] . The patient we reported had obvious symptoms because the tumor was large enough and located in the distal trachea.
CT scans and bronchoscopy represent the main diagnostic tools for this disease, but the misdiagnosis rate of bronchoscopy biopsy is relatively high. Hsieh et al. reported that in a retrospective study of 41 cases of pulmonary MEC, only 4 patients had an accurate preoperative diagnosis from bronchoscopic biopsy [9] ., which may be related to factors such as brittle tumors that bleed easily and small or shallow samples. The diagnostic gold standard for MEC is histopathological examination. There is no single immunohistochemical stain that one can de ne as pathognomonic for MEC [1] , but Roden AC et al.
reported that MAML2 rearrangement studies might be helpful in the distinction of MEC from other epithelial lung malignancies [10] . In this case, the tumor shows positive staining with antibodies commonly used for squamous cell carcinoma, such as p63 and CK5/6. In addition, the tumor may also show mild positive staining for CK7 and Ki67; however, the tumor is generally negative for TTF-1 and neuroendocrine markers. All of these ndings are consistent with previous reports [1,[11][12][13] .
A literature search was performed using the PubMed database to determine the availability of all full-text articles on tracheal MEC in English before April 2021. In total, 73 articles involving 83 cases were identi ed (Table 2); there were only 6 cases of tracheal lesions, accounting for 9.5%, and the rest were all derived from bronchial lesions. Therefore, here we report the seventh case of trachea-derived MEC.
Treatment of tracheal MEC depends on its aggressiveness and the extent of its spread. Currently, surgical resection is considered the rst treatment for this disease, which includes pneumonectomy, lobectomy, and sleeve lobectomy [6,14]. Of the 6 cases of tracheal MEC we retrieved, 2 cases were due to worsening upper airway obstruction, and emergency rigid bronchoscopy followed by electrocautery snaring was performed to remove the bulk of the tumor [15,16]. One patient injured the azygous vein and a branch from the right pulmonary artery leading to massive intratracheal bleeding, and an emergency sternotomy was performed. One patient received bronchoscopic polypectomy using a snare to relieve symptoms [17]. The other patient was a woman at 27 weeks of gestation, and she was treated by therapeutic bronchoscopy with argon plasma coagulation [18]. Only 2 patients underwent surgical resection, but no records of anesthesia or surgical procedures were reported [19,20]. In this report, we rst provide a comprehensive description of airway management and anesthesia intubation because this case highlights the challenges with anesthesia and surgical interventions of large airways. Most cases have no recurrence in long-term clinical follow-up after complete tumor resection. Chemotherapy was used for patients with metastasis or inoperable evaluation. Some scholars also treat this disease with Epidermal Growth Factor Receptor (EGFR) inhibitors, suggesting that effective remission, recurrence delay and survival were achieved via EGFR inhibition [3,21].
Important prognostic factors for MEC include histological type, TNM stage, radiation uptake and age [22].
Compared with high-grade MEC, low-grade MEC has a very good 5-year survival rate [23] . Fortunately, low grade MEC is dominant, accounting for 75.8% of the data in our statistics. Due to the rarity of tracheal MEC, there is no standardized approach to postoperative treatment. The majority of low-grade MEC cases were followed up regularly, while a few high-grade MEC cases were followed up with subsequent adjuvant chemotherapy or radiotherapy.
Immunotherapy, especially the use of immune checkpoint inhibitors (programmed death 1/programmed death ligand 1), has revolutionized the management of several different cancer types in recent years, and PD-L1 was reported to predict the response to immunotherapy [4,5] . In normal adult tissue, PD-L1 is constitutively expressed in normal placental trophoblasts as well as choriocarcinomas and trophoblastic components of germ cell tumors. Additionally, some neoplastic cells, such as squamous cell carcinoma of various sites, frequently express PD-L1 [24] . PD-L1 is only rarely expressed in adenocarcinoma cells and is not expressed in pulmonary schwannoma [24,25] . Normal lung parenchyma lacks PD-L1 expression, while lung carcinomas express varying levels of PD-L1 [24,26] ; however, PD-1/PD-L1 expression has never been examined in tracheal MECs. Given the recent use of immune checkpoint inhibitors, as well as different levels of PD-1/PD-L1 expression in different organs, we investigated the PD-1/PD-L1 pathway in this patient. Surprisingly, this tumor was negative for PD-1/PD L1 immunoreactivity, which may indicate that potential adjuvant treatment with immune checkpoint inhibitors would not have been useful in this particular case. Of course, our sample data are too small, and checkpoint inhibitors remain to be tested in large clinical samples.
In summary, we present a case of PD-1/PD-L1-negative tracheal MEC, and describe anesthesia intubation and surgical procedures in detail. This kind of pulmonary malignant tumor is prone to misdiagnosis and missed diagnosis because of atypical clinical symptoms in the early stage. CT and bronchoscopy should be comprehensively applied to identify airway lesions, and patients should be treated as soon as possible.  Notes: CR, complete response; PR, partial response; PD, progressive disease. Figure 1 Preoperative and postoperative lung function test. Notes: (A) preoperatively, the F-V ring presents a characteristic platform shape, suggesting that inspiratory and expiratory ow is signi cantly limited; (B) postoperatively, pulmonary function indicates mild mixed ventilation dysfunction and normal small airway function.