Tracheal chondrosarcoma: A case report, systematic review, and pooled analysis

Abstract Background Tracheal chondrosarcoma is a rare malignancy, and formal treatment guidelines have not been established due to the lack of high quality studies. Best evidence at this time is limited to case reports. Aim Explore the role of surgical intervention, radiation therapy, and chemotherapy, and the long‐term outcomes for these interventions for tracheal chondrosarcoma. Methods and Results A literature search was performed using PubMed (1959–2020) and ResearchGate (1959–2020) using medical subject heading terms “tracheal chondrosarcoma” OR “trachea chondrosarcoma.” Additional reports were identified within reviewed articles and included for review. Articles pertaining to chondrosarcomas of the lung, bronchus, larynx, or other head and neck subsites were excluded. Cases of chondromas were excluded. Thirty‐five patients with tracheal chondrosarcoma were identified in the literature since 1959. Advanced age was significantly associated with recurrent or persistent disease (p = .003). The majority (77%) of cases were treated with open surgical resection, with an open approach and negative surgical margins being significantly associated with being disease‐free after treatment (p = .001 and p < .001, respectively). Adjuvant radiotherapy was reserved for those unfit for surgery or for recurrent disease. Tumor size, extra‐tracheal extension, tumor calcification, location, and initial diagnosis were not associated with tumor recurrence. Conclusion Non‐metastatic tracheal chondrosarcoma can be treated by adequate surgical resection, with little to no role for adjuvant radiotherapy or chemotherapy. Open surgery and negative margins were associated with oncologic control, while advanced age was associated with recurrent or persistent disease.


| INTRODUCTION
Chondrosarcomas are a rare malignancy, comprising only 0.1% of all head and neck cancer. A majority of cases arise from the bony tissue of the face and paranasal sinus cavities, but less commonly arise from the cartilaginous tissues of the larynx or other soft tissue. 1 While tumorigenesis is incompletely understood, head and neck chondrosarcomas have been proposed to arise from malignant degeneration of cartilage remnants, mesenchymal pluripotent cells, ossified cartilage, and from isolated endochondromas. 2 Several syndromes have also been associated with a higher incidence of chondrosarcoma, including Ollier disease, Maffucci syndrome, and Paget's disease of the bone. 2 Within the head and neck, chondrosarcoma of the trachea accounts for an even smaller subset of all chondrosarcomas, with only 34 cases reported in the literature between 1959 and 2020. Because of this, evidence for treatment is limited to these case reports, although surgery has historically been the mainstay of treatment.
To determine appropriate treatment of tracheal chondrosarcomas, we reviewed case reports and case series in the literature that reported on surgical and nonsurgical treatment and outcomes. In this review, we discuss a case of proximal tracheal chondrosarcoma treated at our institution, and report treatment and outcome results of a systematic review and pooled analysis of the available clinical literature. The goal was to assess characteristics of patients with tracheal chondrosarcoma, treatment, and oncologic outcomes.

| MATERIALS AND METHODS
A literature search was performed using PubMed  and ResearchGate (1959-2020) using medical subject heading terms "tracheal chondrosarcoma" and "trachea chondrosarcoma"; these databases were searched on May 13, 2000

| CASE DESCRIPTION
A 66-year-old male with a history of hypertension, type 2 diabetes mellitus, hyperlipidemia, aortic aneurysm, and a remote history of colon cancer presented to the emergency department of our tertiary care academic medical center with an acute onset of hemoptysis and dyspnea. He had reported mildly increased dyspnea with exertion over the past 6 months.

| RESULTS
Our literature search yielded 32 English language publications describing a total of 33 patient reports 3-33 and 5 non-English language publications reports 34-38 describing a total of 5 patients. One case report lacked significant patient data and was excluded. Three pairs of cases described the same case and were consolidated. 9,16,17,22,23,37 Thus, including our own reported case, a total of 35 unique cases were included for analysis. Four patient reports lacked long-term follow up data, and were also excluded specifically from survival analysis. 11,16,17,19,21 All studies were case reports (level 5 evidence).
The demographic and tumor characteristics of these are detailed in Tables 1 and S1. The median age at presentation was 68 years (interquartile range [IQR], 58-75 years), and 91% of patients were male. The most common presenting symptom was dyspnea (80%), and 45% of patients were initially misdiagnosed, most commonly with asthma. The distribution among the proximal, middle, and distal trachea was 54%, 17%, and 29%, respectively. Calcifications were seen in 71% of tumors and 74% showed extratracheal extension on pre-operative imaging (when available). The median tumor size was 3.0 cm (IQR, 2.5-4.0 cm).
Treatment and outcome data are reported in Tables 1 and S1.
Open surgical resection to negative margins was the primary treatment modality in 77% of cases, and of these, only two developed recurrence. Median follow up time was 30 months (IQR, 12-42 months). Endoscopic debulking with or without adjuvant radiotherapy was usually reserved for patients who either refused surgery or were unfit surgical candidates, although this treatment generally resulted in a stable outcome for the patient in spite of residual disease. Chemotherapy was not given in any cases.
For patients in whom long-term follow-up and outcomes were reported, univariate analysis was performed, comparing the group that developed residual or recurrent disease after definitive treatment to the group that did not develop recurrence (Table 1) 13 Dyspnea and cough were the two most common presenting symptoms at 80% and 40%, respectively. Given the nonspecific symptoms and typical lack of external findings, it is unsurprising that many cases are initially misdiagnosed. Although a majority (55%) of patients were correctly diagnosed with a tracheal mass at the time of presentation, 29% were incorrectly diagnosed as asthma or COPD exacerbations, and 9% with thyroid masses. In four cases, the diagnosis of chondrosarcoma was made in the context of a previously known tracheal endochondroma, 9,10,24,33,37 which is consistent with reports of malignant transformation of chondromas in other parts of the body. 39 In one case, 9,37  Attempted shave resection or endoscopic resection is not recommended, except in cases of temporization or palliation of the airway. Only one patient was reported to have been successfully cleared of his disease endoscopically, though notably this tumor was described as pedunculated. 3 Endoscopic resection was significantly more common in the group developing residual or recurrent disease (75% vs. 9%, p = .001), likely due to incomplete surgical resection. All but two patients developing recurrence or progression of their disease had grossly residual disease after their definitive surgical intervention, 4,13,24,25,30,33 and the proportion of those with residual disease was significantly greater in this group compared to those not developing recurrence (75% vs. 4%, p < .001), highlighting the importance of obtaining adequate oncologic margins.
Adjuvant radiation therapy (RT) has thus far played only a limited role in tracheal chondrosarcoma management, as they are generally considered to be radioresistant. The one patient who underwent 50 Gy of adjuvant conformal RT in spite of reported surgical clearance of his disease ultimately developed local recurrence of his chondrosarcoma $4 years later, which was successfully treated by re-resection. 38 The remaining instances in which RT was Our study has limitations. Because of the rarity of the disease, all included studies were limited to case reports. Many of these, especially earlier-published reports, lacked important data about tumor characteristics, treatments, or outcomes; more consistent reporting is needed.

| CONCLUSION
As most tracheal chondrosarcomas present as low grade, nonmetastatic tumors, they are treatable with surgical resection alone, which results in long-term oncologic cure in most cases. Available evidence suggests radiotherapy and chemotherapy are generally not indicated, although they could be considered for advanced disease or in cases where surgery is a contraindication. Given the rarity of the condition, future cases of tracheal chondrosarcoma should be rigorously reported to allow for better characterization of its presentation, appropriate treatment, and outcomes.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

ETHICAL STATEMENT
The subject of this case report has given consent to participate and to publish this account. The institutional board review was not required at our institution. writingreview and editing.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.