Squamous cell carcinoma and adenoid cystic carcinoma are the most common tumors of the tracheobronchial tree. Granular cell tumors of the tracheobronchial tree are extremely rare, with an estimated population-based incidence of only 2:100,000. Approximately, 5.3% of GCTs were in the tracheobronchial tree in our series, which is slightly lower than previous research results [5, 8]. The age range was five to 84 years, and these tumors tended to occur classically in middle-aged patients, with a mean age of 42 years. Among the patients with tracheal GCTs (mean age 35 years; range 6-77), while among those with bronchial GCTs (mean age 51 years; range 5-84)[5, 14–17]. The mean age of the patients with tracheal GCTs was lower than the mean age of those with bronchial GCTs. Tracheobronchial GCT involvement in children is exceedingly rare [5, 14, 17]and a 15-year-old girl with a tracheal GCT was reported in our study. Tracheal tumors are more prevalent in women, and bronchial tumors are seen equally in males and females. The mean size of the neoplasm at the time of diagnosis was 2.0 cm, with a range from 0.05 to 6 cm in its large axis[5, 18, 19]. The mean size of tracheal tumors is twice as large as that in the bronchus, which may be related to their anatomical structure  Consistent with our cases, most of these cases were solitary but could be multiple in 7-25% of cases. Regarding the site, tumors are more likely to occur in the bronchus. Bronchial GCTs were equally distributed over both lungs and showed a preference for the upper lobes . In contrast, GCTS occurred more frequently in the trachea (75%) in the present study.
The clinical presentations of the patients vary depending upon the size and location of the tumor. Most of the patients presented with cough, dyspnea, asthma, hemoptysis, and pneumonia, while others were asymptomatic and diagnosed incidentally. Patients in our studies often presented with cough. It is worth mentioning that three of four cases suffered from lung infection. Patients with cigarette smoking are frequently noted . However, only one patient in our cases had a smoking history of at least 10 pack-years. The index case also had a history of cigarette smoking, but because of the small number of patients and insufficient database, the association between GCTs and smoking was not clearly established. Bronchoscopy showed that tracheal GCTs appear more frequently as pedunculated polypoid lesions with intact mucosa partially obstructing the tracheal lumen. On imaging studies, these tumors can present as bronchial obstruction, coin lesion or hilar mass. In our study, half of the cases were considered to be lung infections on chest CT examination, which were confirmed after bronchoscopy. Bronchoscopy is recommended as the diagnostic test of choice because it is particularly helpful in evaluating the presence of intraluminal tracheobronchial lesions and can facilitate diagnosis with biopsy.
The immunohistochemical profile of GCTs has undergone extensive analysis. It is well established that granular cell tumors are positive for S-100 protein. In addition to the S-100 protein, positive expression of CD68, which is a histiocytic marker in GCTs, indicates intracytoplasmic lysosomes in this otherwise neural sheath-derived tumor, which is best regarded as a GCT[23, 24]. In the present study, S100 protein, CD68 and Nestin expressions were noted in all sites of cases where it was performed. In corroboration with a recent study by Parfitt et al. , we show that all GCTs were positive for Nestin. GCTs exhibited a relatively lower ratio of calretinin expression in both the tracheobronchial tree and esophagus, while positive calretinin expression was detected in 100% of GCTs originating from subcutaneous tissues in our study, which is similar to previous studies . In contrast to the results of Brian et al. and Murakata et al., none of the GCTs in our study expressed α-inhibin. Although calretinin expression in a GCT has been attributed to a neural lineage, the reasons for α-inhibin positivity have yet to be clarified. It is known that tumors of the peripheral nerves are negative for inhibin-α . Whereas most investigators have identified that nearly 100% of GCTs are inhibin-α positive, others have reported variable cytoplasmic inhibin-α positivity[9, 24–27]. These discrepancies appear to be independent of the antibodies used and may be the result of other methodological differences between laboratories.
TFE3 is a member of the helix-loop-helix family of transcription factors and is considered a useful marker in alveolar soft part sarcoma (ASPS) and Xp11.2 translocation cancer diagnostics, including Xp11.2 translocation-associated renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor and melanotic Xp11 translocation RCC. Some previous studies have revealed that more than 90% of GCT cases have diffusive and marked positivity for TFE3 by Chamberlain et al. and Schoolmeester et al. [9, 10]. To the best of our knowledge, only one case of primary tracheal GCT with TFE3 expression was reported by a previous study Recently, Yang Liu et al. demonstrated that only 11/45 (24%) cases with TFE3 overexpression and 13/45 (29%) cases with focal or weak TFE3 staining in Chinese patients were lower than those in occidental patients according to previous studies. They also identified that GCTs in subcutaneous tissue exhibited a relatively higher ratio of TFE3 expression than those in other sites . In the present study, GCTs in the tracheobronchial tree, subcutaneous tissue and esophagus exhibited a ratio (1/4, 25%),(3/4༌75%)and༈3/3༌100%༉ for TFE3 expression, respectively. In contrast to the results of Chamberlain and Schoolmeester, GCTs in the tracheobronchial tree exhibited a much lower ratio (1/4,25%) of TFE-3 expression, which showed only weak focal staining. Compared with these studies, positive TFE-3 expression was detected in 86% (6/7) of GCTs in the control group originating from the subcutaneous tissue and esophagus. This finding may reflect a site-specific phenomenon distinguishing GCTs of the tracheobronchial tree. However, no rearrangement or amplification of TFE3 was identified in these tumors according to FISH data [9, 29]. As a possible explanation, Chamberlain et al. proposed that aberrant nuclear TFE3 accumulation could be caused by organelle or intracellular metabolic signaling pathway dysfunctions, which could lead to the typical cytoplasmic accumulation of phagolysosomes in GCTs .
Microscopically, these tumors are unencapsulated, often infiltrating surrounding tissues. They are composed of cells with abundant eosinophilic granular cytoplasm with a small and uniform nucleus. Granular cell tumor cells were mainly round and polygonal; however, spindled and fascicular characteristics were also present in several tumors. Fanburg-Smith et al. proposed six diagnostic criteria for malignant GCTs: (1) necrosis, (2) spindling, (3) brisk mitotic activity, (4) a high nuclear to cytoplasmic ratio, (5) vesicular nuclei with prominent nucleoli and (6) pleomorphism. The presence of three or more of the following features suggests malignant GCTs. If the specimen exhibits one or two of these features, it is classified as atypical GCT. In the present study, one sample exhibited a fusiform or spindled morphology, which should be classified as atypical GCT. Some scholars believe that malignant GCTs can only be determined when metastasis occurs. According to statistics, approximately 98% of GCTs are benign lesions, and tracheobronchial malignant GCTs are very rare. Although extremely rare, it is possible that pulmonary GCTs can be malignant; the first case of malignant pulmonary GCT was reported in 2003. The differential diagnosis of GCT includes all subglottic masses. Benign and malignant tumors of the trachea, along with esophageal, thyroid, and mediastinal tumors, should be considered. The majority of tracheobronchial tumors in adults are malignant and include squamous cell carcinoma, adenoid cystic carcinoma, neuroendocrine tumors (large cell neuroendocrine tumors and small cell carcinoma), alveolar soft tissue sarcoma and metastases. However, various benign tumors, such as neurilemmoma, leiomyoma, hemangioma, benign fibrous histiocytoma and carcinoid tumors, should also be considered.
In our series, retreatment with one patient was indicated, and the majority of the patients were in complete remission after the first treatment. Patients treated with surgery remained in remission for up to 10 years. Even patients with residual disease continued to live with stable disease, which indicates a very benign course. There is a high recurrence rate when these tumors are removed either endoscopically or by laser therapy. Incompletely excised lesions have a recurrence rate of 0–12%. It is therefore advocated that lesions should be completely excised when possible if morbidity is minimal. Close follow-up once a year for at least 5 years is recommended in GCTs, especially in lesions treated with biopsy or subtotal resection.