Tracheal mucosal keratosis: Case discussion and literature review

Abstract

A 57-year-old female presented with a chief complaint of cough, with productive yellow sputum particularly severe in the morning. Bronchoscopy revealed inflammatory changes in both main bronchi, with abundant white purulent secretions and necrotic material adhering to the luminal surface. Histopathological examination showed chronic inflammatory changes in the mucosal tissue, with mild hyperplasia of the local squamous epithelium and evidence of keratinization in the surrounding area, consistent with a diagnosis of tracheal mucosal keratosis. The patient was treated with anti-infection therapy, combined with symptomatic supportive treatments such as cough suppression, expectorants, and bronchodilation, resulting in an improvement of symptoms. Analysis of previous literature revealed that although this condition lacks specific clinical manifestations and signs, it exhibits a typical pattern of tracheal wall lesions, and bronchoscopy and histopathological examination have high diagnostic value for this disease. Due to impaired airway mucosal barrier function, the patient is prone to bacterial infection or colonization in the airways. Symptomatic supportive treatment based on the actual condition can effectively alleviate the patient’s clinical symptoms. Currently, there is no definitive curative treatment for tracheal mucosal keratosis. However, treatments such as high-frequency electrocautery, carbon dioxide cryotherapy, and repeated lavage with epidermal growth factors may be helpful in curing this condition.

Clinical data

A 57-year-old female patient was admitted to our department with a complaint of “cough and expectoration for over 6 months” on July 17, 2021. The patient reported that the cough and yellow sticky sputum started half a year ago, particularly worsening in the morning. However, she did not experience fever, hemoptysis, or any other accompanying symptoms, and her daily activities were not hindered. The patient denied any history of chronic diseases, such as diabetes or hypertension, as well as any previous infectious diseases, smoking, or alcohol consumption.

Upon physical examination after admission, the patient exhibited a body temperature of 36.4°C, a heart rate of 92 beats/min, a respiratory rate of 20 times/min, and a blood pressure of 117/74 mmHg. Bilateral lung breath sounds exhibit coarse with slight adventitious crackles. No abnormalities observed in other parameters.

Auxiliary examination results: Blood routine within normal range; Liver and kidney function: total cholesterol 5.55 mmol/L (normal <5.18 mmol/L), uric acid 348.0umol/L (normal range 142.8-339.2umol/L), urea 8.0 mmol/L (normal range 2.6-7.5 mmol/L), high-sensitivity C-reactive protein 30.3 mg/L (normal value <1 mg/L), erythrocyte sedimentation rate 31 mm/h (normal range 0-20 mm/h). Other items are within the normal range.

On July 19, 2021, chest CT revealed multiple nodular opacities in both lungs. The largest one was located in the right middle lobe, measuring approximately 27 mm × 15  mm with clear borders. The lingular segment of the left lung showed increased density in a linear pattern, associated with bronchial traction and dilatation in the surrounding areas. A calcified lesion was observed in the lower lobe of the right lung. Additionally, there was thickening and adhesion of the pleura on both sides.(Figure 1 (A)-(C))Bronchoscopy performed on July 20, 2021 revealed no apparent abnormalities in the visible range of the larynx. In the trachea, carina, and bilateral main bronchi, there was an abundance of white purulent secretions and necrotic material adhering to the luminal surface. The mucosa appeared congested with uneven surface contour, while the luminal patency was maintained. No apparent abnormalities were observed in the other branches (segments and subsegments) of the bilateral bronchi (Figure 2). A biopsy specimen was taken from the distal end of the right main bronchus and sent for pathological examination. The results revealed chronic inflammatory changes in the mucosal tissue, with mild squamous epithelial hyperplasia and areas of excessive keratinization in some regions. (Figure 3). Bronchoscopy cytology examination: Under the microscope, ciliated columnar epithelial cells, squamous epithelial cells, lymphocytes, and neutrophils were observed. Occasionally, enlarged nuclei were seen, but no malignant cells were found. Acid-fast bacilli were not detected in bronchoalveolar lavage fluid(BALF) or sputum smears. The culture results of BALF showed the presence of Pseudomonas aeruginosa and Klebsiella Pneumoniae. The susceptibility test indicated that the pathogenic bacteria are sensitive to beta-lactam antibiotics and quinolone antibiotics. Pulmonary function tests revealed a decline in mid-to-late expiratory flow velocity, with a negative response to provocation tests. No other specific abnormalities were observed. Based on the above examinations, the patient is diagnosed with tracheal mucosal keratosis. According to the results of the susceptibility test, the patient was treated with a combination of cefoperazone-tazobactam and levofloxacin for infection, along with ipratropium bromide nebulization for cough relief and expectorant treatment. After the patient’s condition improved, she requested to be discharged from the hospital. Upon discharge, the patient will continue to take acetylcysteine effervescent tablets orally on a regular basis, as well as follow the doctor’s advice to perform respiratory exercises and engage in activities such as jogging. The patient will also maintain the habit of wearing masks in crowded places.

Figure 1.

A: Chest CT scan on July 2021: Lung window of the upper lobes (with visible irregularity in the tracheal wall). B: Chest CT scan on July 2021: Mediastinal window of the upper lobes (at the same level, showing slight thickening of the airway mucosa). C: Chest CT scan on July, 2021, a lesion in the middle lobe of the right lung. D: Chest CT scan on April, 2022, a lesion in the middle lobe of the right lung.

Figure 2.

July 20, 2021, electronic bronchoscopy examination. A: trachea. B: carina. C: Left upper and lower lobe junction. D: right bronchus.

Figure 3.

Airway mucosal pathology. A: Mild local squamous epithelial hyperplasia. B: Partial mucosal hyperkeratosis.

On March 27, 2022, the patient experienced worsening cough symptoms with the production of moderate amounts of yellow sputum after exposure to smoke. On April 20, 2022, a follow-up chest CT scan revealed a reduced lesion in the right middle lobe compared to July 2021 (Figure 1(D)).

On March 31, 2022, a bronchoscopy examination was performed, revealing no significant abnormalities in the larynx. However, the mucosa of the trachea, carina, and right main bronchus appeared uneven with a significant amount of necrotic material adhering to the surface. No obvious abnormalities were observed within the range of the left bronchus (Figure 4). Compared to the results of the electronic bronchoscopy examination on July 20, 2021, there is a reduction in the amount of necrotic material adhering to the surface of the airway mucosa. Cytological examination of the bronchial brush specimens revealed a few neutrophils and occasional superficial squamous epithelial cells, with no evidence of tumor cells. Next-generation sequencing of the BALF indicated the presence of Klebsiella Pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The patient was treated with levofloxacin in combination with biapenem for targeted antimicrobial therapy, and her condition stabilized before discharge.

Figure 4.

March 31, 2022: electronic bronchoscopy examination. A: trachea, B: carina, C: left bronchus, D: right bronchus.

Discussion

Tracheal mucosal keratosis is a rare respiratory disease. A summary of all literature related to this condition (Table 1) suggests that it primarily affects adult males with an average onset age of 41.5 years.^1–18 There have also been reports of this condition in children. ¹³ The majority of patients have no apparent triggering factors, and the present case patient also has no significant medical history.

Table 1.

Clinical data of 22 patients with tracheal mucosal keratosis.

Clinical features	Sample size	Percentage	Clinical features	Sample size	Percentage
Age(years)			Lesion site
<18	1	4.5	Trachea	22	100.0
≥18	21	95.5	Left/right main bronchus	15	68.2
Gender			Biopsy pathology results
Male	16	72.7	Inflammatory infiltration	17	77.3
Female	6	27.3	Squamous metaplasia	21	95.5
Trigger			Mucosal keratinization	21	95.5
Interior decoration	1	4.5	Bacterial culture
Dust exposure	1	4.5	Positive	17	85.0
Irritating odor	2	9.1	Negative	3	15.0
Smoking	4	18.2	Treatment plan
Grazing	1	4.5	Antimicrobial therapy	21	95.5
No apparent cause	13	59.1	Symptomatic treatment	3	13.6
Symptoms/ Signs			Vitamin	1	4.5
Cough & phlegm	20	90.9	Cryotherapy	1	4.5
Chest pain/ tightness	10	45.5	Electrocautery	1	4.5
Breathing difficulties	2	9.1	Irrigation therapy	1	4.5
Hoarse voice	2	9.1
Snoring	2	9.1

The majority of patients present with cough, sputum production, chest pain, and chest tightness. The sputum is commonly white or yellowish, occasionally gelatinous^1,18 or purulent, ³ and hemoptysis is rare. ¹⁵ A small number of patients exhibited the retraction sign and audible snoring.^2,5 X-ray and chest CT scans often show no abnormalities or may reveal bronchitis or pneumonia. Pulmonary function tests may indicate obstructive ventilation impairment in some patients.^5,10 Bacterial cultures of sputum and BALF frequently yield positive results for Pseudomonas aeruginosa,^{10,13–15,17} while other pathogens like Klebsiella pneumoniae, Stenotrophomonas maltophilia, Morganella, Aspergillus, and Streptococcus pneumoniae can also be detected. Unlike other patients with tracheal mucosal keratosis who often present with various accompanying symptoms, this case patient only exhibited cough and sputum production, making it easily misdiagnosed, and BALF examinations indicate the presence of Klebsiella pneumoniae, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa.

Summary of bronchoscopy findings reported in the current cases: Typical tracheal mucosal keratosis is characterized by normal epiglottis and vocal cords. The tracheal mucosa, as well as the surfaces of the left and right main bronchi, exhibit widespread distribution of yellow-white plaques. These plaques vary in size and have irregular shapes, resembling cobblestone-like changes. In some patients, the posterior wall of the pharynx, the area of the aryepiglottic fold, and the area above and below the vocal cords are also affected. ¹ However, in other patients, no similar changes have been observed in the bronchi below the bifurcation of the carina.^1,2 The plaque has a tough texture and is not easily grasped or removed by irrigation. Mechanical friction using a bronchial brush can be used to treat it, and biopsy is less likely to cause bleeding. ⁸ However, this should be excluded if there is congestion, swelling, or erosion of the tracheal mucosa. ¹² The typical histopathological findings of this condition include squamous metaplasia of the tracheal mucosa with excessive keratinization, excessive keratinization in certain areas, mild proliferation of spinous layer cells, intact and non-dysmorphic basal cells, abundant inflammatory secretions and infiltration of various inflammatory cells in the stroma. ¹ The typical bronchoscopic and histopathological findings of tracheal mucosal keratosis are consistent with the presentation in this case.

To date, there is no unified standard for the treatment of tracheal mucosal keratosis. As is well known, the epithelial cells of the trachea and bronchi exhibit pseudostratified morphology and are primarily composed of three cell types: ciliated cells, goblet cells, and basal cells. Ciliated cells promote the movement of mucus in the airways, goblet cells produce and secrete mucus, and basal cells can differentiate and replenish the epithelial cell layer following airway epithelial damage. A intact epithelial cell layer is crucial for maintaining lung homeostasis and host defense. ¹⁹ Patients with tracheal mucosal keratosis often exhibit yellow-white nodules and plaque formation on the luminal surface of the airway. Congestion and swelling of the tracheal mucosa are commonly observed, and some patients may also present with mucosal erosion. The loss of epithelial integrity in patients with tracheal mucosal keratosis makes them more susceptible to bacterial colonization and invasion when exposed to infections, pollutants, chemical exposure, and allergens, subsequently triggering airway inflammation. This can also explain the recurrent disease exacerbation in the present case, triggered by exposure to cold and inhalation of smoke. Therefore, in the past two decades, in clinical practice, symptomatic supportive treatment such as anti-infection therapy and expectorants are mainly used to alleviate symptoms in patients with this condition. Other co-administered treatment methods include vitamin supplements,^4,18 glucocorticoids, and traditional Chinese medicine based on syndrome differentiation. ⁸ For patients with poor lung function and obstructive ventilatory dysfunction, bronchodilators should also be administered to improve ventilation. There is currently no definitive evidence to suggest that these methods can cure tracheal mucosal keratosis. Further research and clinical studies are necessary to explore more effective treatment options for this condition. It is worth mentioning that the airway mucosal keratosis of three patients was significantly improved after treatment. The first patient received bronchoscopic high-frequency electrocautery during hospitalization, and follow-up results after 4 months of discharge showed the disappearance of keratinized lesions. Additionally, there was no recurrence observed during a 10-month follow-up. ² The second patient underwent bronchoscopic argon plasma coagulation and carbon dioxide cryotherapy during hospitalization, supplemented with vitamin A and D for mucosal repair after discharge. One year later, the follow-up chest CT scan showed reduced calcification, thickening, and irregular narrowing of the tracheobronchial wall, with the restoration of normal airway mucosa. The patient’s condition remained stable during a 2-year telephone follow-up. ¹⁷ The third patient received fiberoptic bronchoscopy-guided repeated irrigation with sodium bicarbonate, dexamethasone, and recombinant human epidermal growth factor. Six months later, the follow-up examination showed complete disappearance of necrotic tissue under the microscope, and there was no recurrence during a 4-year follow-up. ¹¹ By comparison, it is evident that high-frequency electrocautery surgery, as well as emerging therapies such as carbon dioxide cryotherapy and epidermal growth factor irrigation, have achieved greater benefits than conventional conservative treatments in recent years. High-frequency electrocautery, by converting electrical energy into thermal energy, can be used for hemostasis, tumor removal, tissue cutting, lesion removal, and wart removal. It is widely applied in the treatment of skin lesions and cosmetic surgeries. The principle of carbon dioxide cryotherapy is to apply liquid or solid carbon dioxide to the affected area, using low temperatures to destroy or remove abnormal tissue. It has been previously used for the treatment of skin injuries or lesions. Epidermal growth factors enhance the skin’s innate immune defense and also inhibit excessive activation of keratinocyte pro-inflammatory functions involved in the formation of keratinized cells. However, given the limited number of cases where these treatment options have been applied to airway mucosal keratosis, their safety and effectiveness still need to be evaluated. In view of the above factors, the patient finally chose drug conservative treatment. The patient in this case was effectively managed with antibacterial therapy using cefoperazone-tazobactam and levofloxacin, as well as symptomatic supportive treatment with ipratropium bromide nebulization for cough relief and expectoration. In addition, long-term regular oral administration of acetylcysteine effervescent tablets, adherence to respiratory exercises, jogging for enhanced physical activity, and wearing masks in crowded areas have also shown positive effects on controlling the patient’s symptoms. It is worth noting that there has been some improvement in tracheal mucosal lesions compared to 8 months ago, but further research is needed to establish the correlation between the improvement of airway mucosal lesions and these measures.

In conclusion, tracheal mucosal keratosis has a low incidence rate and no obvious occupational predisposition. The onset of the disease may be associated with irritant odors, dust, and smoking. Patients lack specific clinical manifestations and physical signs, and imaging examinations such as X-rays and chest CT scans are also difficult to provide a definitive diagnosis. Given the typical airway wall lesion pattern associated with tracheal mucosal keratosis, bronchoscopy and histopathological biopsy have the highest diagnostic value for this condition. During bronchoscopy, it is important to differentiate from several types of diseases. Firstly, diseases that can easily form nodules and masses in the tracheal lumen include lung cancer, bronchial amyloidosis, and bronchial tuberculosis, among others. Lung cancer commonly presents with symptoms such as cough, chest pain, and hemoptysis as the initial manifestations. Performing a biopsy of the lung tissue mass can aid in the differentiation of lung cancer. When amyloidosis involves the bronchi, the main manifestations are respiratory difficulties and hemoptysis. Immunohistochemical staining can assist in the diagnosis, and histopathological examination remains the gold standard for diagnosis. For bronchial tuberculosis, diagnosis typically requires supplementary pathogen examination results. Secondly, it is necessary to differentiate from tracheobronchopathia osteochondroplastica (TO), in which patients have increased bone and cartilage proliferation beneath the tracheal and bronchial mucosa, protruding into the lumen. Tracheal mucosal biopsy reveals squamous metaplasia of the epithelium, but no evidence of keratinization is observed. Thirdly, it is important to differentiate from bronchial fungal infections. A definitive diagnosis can be made by culturing the respiratory secretions or performing histopathological examination to identify fungal or mold spores or hyphae. By summarizing relevant case reports, this article aims to enhance the understanding of clinicians regarding this disease. It is believed that through the accumulation and exchange of case data, our diagnostic and treatment capabilities for this disease will continue to improve.