Survival outcomes in laryngeal chondrosarcoma: a systematic review| ACTA Otorhinolaryngologica Italica

Abstract

Laryngeal chondrosarcomas (LCS) are rare lesions that behave as locally aggressive tumours, producing symptoms such as dysphonia, dyspnoea, dysphagia and hoarseness. Different approaches for the treatment of LCS have been described in the literature. The main purpose of this investigation was to find all cases of LCS published to date and analyse management data and survival outcomes. In December 2020, a systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Provider Enrollment, Chain, and Ownership System (PECOS) method including articles published up to this date on different aspects of LCS. The search included the terms larynx, laryngeal, chondrosarcoma. A total of 148 articles were included in this systematic review describing 381 cases of LCS. Dyspnoea was the most reported symptom followed by hoarseness and neck mass sensation. Cricoid cartilage was the most usual location. Survival rate was influenced by both surgical technique (logrank = 11.7; p = 0.008) and the degree of tumour histologic differentiation (log-rank = 18.3; p = 0.003).

Introduction

Chondrosarcomas (CS) are cartilaginous tumours that commonly affect bones including the pelvis, ribs and femur ¹. They may also affect the larynx, with the cricoid cartilage being the most common site of appearance. Nevertheless, CS can also originate in thyroid or arytenoid cartilages, epiglottis or even hyoid bone ².

Laryngeal chondrosarcomas (LCS) are extremely rare tumours, representing less than 1% of all malignancies of the larynx ³. LCS behave as locally aggressive tumours, producing symptoms such as dysphonia, dyspnoea, dysphagia and hoarseness. In other cases, they can also appear as a neck mass. Computed tomography (CT) and magnetic resonance imaging (MRI) are the imaging modalities preferred to make a presumptive diagnosis ⁴, although F-18 fluorodeoxyglucose-positron emission tomography (PET) may be used for grading, and for detection of local recurrence or metastases ⁵. Fine needle aspiration (FNA) or incisional/excisional biopsies may support initial diagnosis ⁶. As surgical treatment may be necessary in most cases, histopathological report of tissues will determine the final diagnosis. CS are classified in 3 grades; Grade I, (low-grade, well-differentiated), Grade II (intermediate grade, moderately differentiated) and Grade†III (high-grade, poorly differentiated). There are different subtypes of CS such as clear cell, mesenchymal, extra-skeletal and dedifferentiated (also considered as Grade IV) CS ⁷.

Different approaches for the treatment of LCS have been described in the literature ^8-11. Treatment varies depending on the grade of differentiation of the tumour and anatomical involvement, from organ preservation techniques to total laryngectomy. Radiotherapy (RT) can be considered in some inoperable patients, for recurrences or in case of aggressive tumours ⁵. Disease-specific survival of LCS is higher compared with other laryngeal tumours ^3,12. The main purpose of this research was to find all the cases of LCS published to date and analyse management data and survival outcomes.

Materials and methods

Systematic review. Protocol and registration

The systematic review was carried out by OACI and was registered in PROSPERO (Ref. CRD42021224412). The review was designed following PRISMA guidelines ¹³ and the PECOS method: patients with LCS (P = patient); histopathologic analysis (E = exposure); non-laryngeal location (C = comparator); clinical-pathological aspects (O = outcome); case reports (S = type of study).

Eligibility criteria: studies describing cases of LCS written in Spanish or English language.

Exclusion criteria: letters to the editor, meetings proceedings and articles with no abstract or full text available.

A comprehensive literature search was performed using the PubMed, Web of Science, Scopus and Embase databases for studies published from January 1968 to December 2020.

The search included the terms “Larynx [MeSH terms] OR Laryngeal [MeSH terms] OR Larynx [Title/Abstract] OR Laryngeal [Title/Abstract] AND Chondrosarcoma [MeSH terms] OR Chondrosarcoma [Title/Abstract]”.

Study selection and data collection process

Two independent researchers (OACI and MPS) analysed the articles. First, they read the abstracts and excluded those not fulfilling inclusion criteria. After that, both authors analysed the full-text and decided whether they should be included or excluded. A third investigator (ALP) acted as a mediator in case of dispute. Agreement was calculated using Cohen’s kappa coefficient (obtaining a k value of 0.92).

Data items

The following information was extracted from each study: first author, year of publication, journal, sex and age of the patient, symptoms, imaging technique, treatment modality, histopathological diagnosis, location, tumour size, recurrence, and follow-up data. References of the selected articles were also checked.

Risk of bias in individual studies

The methodological quality of the included studies and the possibility of bias were assessed using the modified Newcastle–Ottawa, Pierson and Bradford Hill scales for case and case series reports ¹⁴. The authors of this scale recommend assessing the quality of studies according to four categories, selection, ascertainment, causality, and reporting, with eight specific questions to answer giving low (1-3 questions), medium (4-6 questions) and high (7-8 questions) quality values. This analysis was carried out independently by each of the two investigators, and in case of disagreement, the third acted as a mediator.

Results

Systematic review

A total of 148 articles were included in this systematic review (Flowchart, Fig. 1) (Tab. I and continuation in Suppl. Material), describing a total of 381 cases of LCS. In terms of quality, the articles were classified within medium quality values. From articles where gender was specified (342/381), 74% percent were men and 25% women, with a mean age of 61.1 ± 12 years.

Regarding symptoms, a total of 325 patients (85.3%) described some symptom before diagnosis, with dyspnoea being the most reported (42.8%), followed by hoarseness (35.7%) and neck mass sensation (10.8%). Most of the patients reported more than one symptom. Impairment of at least one vocal cord mobility was reported in 66 patients (17.3%). Imaging studies were described in 213 patients (55.9%). CT scan was the most used (n = 209) followed by MRI (n = 46). Other techniques such as ultrasound or X-ray were also described. In Table II, categorical data reported in the included studies are summarised.

Tumour site was reported in 340 patients (89.2%). The cricoid cartilage was the most affected with 271 cases (79.9%), followed by the thyroid cartilage in 67 cases (19.7%). In 41 patients (10.8%), the tumour involved more than one anatomical site.

Different treatment modalities were used. Total laryngectomy was reported in 131 patients (34.4%), tumour excision in 104 cases (27.3%), partial laryngectomy (hemicricoidectomy, cricoidectomy, cricotracheal resection, or vertical, supraglottic, supratracheal, supracricoid laryngectomy) in 92 (24.1%), and laser surgery (Carbon Dioxide, Nd Yag or KTP laser) in 34 patients (8.9%). Radiotherapy was used in 7 patients (1.8%) as the first treatment. Adjuvant therapy with RT was delivered in 28 patients (7.34%) and chemotherapy in 2 patients (0.52%). The size of the tumour was reported in 135 patients (35.4%), with a mean size of 3.8 ± 1.7 cm. Histological information was found in 323 patients (84.7%). Pathological grading was reported as Grade I (well-differentiated) in 210 cases (70.5%), Grade II (moderately differentiated) in 62 cases (20.8%), Grade III (poorly differentiated) in 8 cases (2.7%) and Grade IV (dedifferentiated) in 18 cases (6.0%). Other cases were reported as clear cell CS, or myxoid CS. Distant metastases were infrequent, and reported in 21 patients (5.5%) in different locations including the lungs, soft tissue, bone or peritoneum. Lung metastasis was the most frequent location, being present in 15 cases (71.4 %).

The mean follow-up time was 57.7 ± 53.4 months. In this period, tumour recurrence was reported in 62 cases (16.3%). Forty-two percent of recurrences corresponded to grade I CS, 14.5 % to grade II CS, 8% to grade III CS and 9.6 % to grade IV or dedifferentiated CS. Total laryngectomy was the treatment of choice in 25 of the recurrences (40%). Local excision and laser were used in 18 patients (29%) while partial laryngectomy was described in 8 patients (13%). Death was reported in 47 patients (12.3%), mostly as “not related or other cause” (74%), or “distant metastasis” (17.4%). Only 8.7% were reported as “died of disease”.

Using Kaplan-Meier curves, a mean survival of 207.5 months (95% confidence interval, CI 176.4-238.7 months) is estimated for the entire series.

Regarding survival in relation with tumour location, the estimate is lower for cases with combined location, with 98.5 months (95% CI 73-124 months) compared to those affecting only one location, with a mean of 191.6 months (95% CI 163.1-220 months) (log-rank = 6.6, p = 0.01).

Survival was also affected by histological differentiation, being the lowest for grade IV (dedifferentiated) with 118.7 months (95% CI 64.8-172.6 months) and the longest for grade I (well-differentiated) with 253.8 months (95% CI 215-292.5 months) (log-rank = 18.3; p = 0.003) (Fig. 2).

Regarding treatment modality, the estimate for survival was lower for those who underwent total laryngectomy with 156.6 months (95% CI 127.5-185.6 months) compared with those who were treated with laser excision with 276.1 months (95% CI 229.4-322.9) (log-rank = 11.7; p = 0.008) (Fig. 3). Death was found to be more frequent in patients with recurrence who were treated with total laryngectomy (55.3%, p = 0.001).

Discussion

A total of 148 articles were included in our study. The results of this systematic review, in general, agree with the main previously published series ^3,15. Thus, LCS are rare tumours, with a male predominance and an average age of appearance between 60-70 years. Histologically, low-grade CS are the most common, with a slow-growing tumour pattern. In some cases, biopsies may misdiagnose Grade I LCS as chondromas. Intermediate and high-grade LCS are less common and usually have the worst prognosis. The results of this systematic review show that survival rate in grade IV LCS was lower than in Grade I LCS.

Symptoms depend on the site and extent of the tumour, generally appear insidiously, and may persist for years before a final diagnosis is made ¹⁶. Due to this indolent behaviour and, to the usual submucosal growth, diagnosis may be delayed in time. Dysphonia and hoarseness are the most frequent complaints of the patients with LCS. Most cases arise from cricoid cartilage, mainly involving the posterior lamina and cricoarytenoid joint. It is not uncommon that LCS may affect different locations at the same time (referred to as combined location herein). In fact, the survival estimate is lower in those patients with involvement in more than one site, compared to those with a tumour involved in only one ⁵.

Surgery is the treatment of choice for LCS. The selection of the surgical technique will depend on different factors such as anatomical involvement, mobility of the cricoarytenoid joint or histological grade of the tumour. The key to choose the appropriate technique is to balance the oncological (loco-regional cancer control) with functional outcomes ¹⁷. Since these tumours are generally associated with good prognosis, the goal should be to remove the tumour with adequate margins avoiding local recurrences or distant metastasis and trying to preserve as much laryngeal function as possible. For this reason, surgeons have described different conservative surgical techniques, including minimally invasive local resections, transoral laser procedures, and partial laryngectomies. Theoretically, less aggressive techniques are indicated for low-grade, not extensive tumours, and those that affect thyroid, arytenoids, and epiglottis or less than a half of the cricoid cartilage. Nevertheless, treatment of cricoid CS is still controversial. Trying to avoid radical, non-functional, management of cricoid CS, some authors reported their results with conservative techniques. In this sense, Damiani et al. ¹⁸, emphasised the use of techniques like “Remodeling Transoral Laser Surgery”, or “Supratracheal Partial Laryngectomy”, in low-to intermediate cricoid LCS, achieving good laryngeal function with minimal risk of recurrence. De Vincentiis et al. ¹⁰, in their series of 3 cricoid CS affecting more than 50% of the cricoid ring, reported that “total cricoidectomy with thyrotracheopexy” is an effective alternative to total laryngectomy. Loos et al. ¹⁹, reported good oncological and functional results in 7 patients with cricoid CS, after “hemilaryngectomy with tracheal autotransplantation”. Piazza et al. ⁸ also reported good results with “open partial laryngectomy” and “cricotracheal resections and anastomosis”. Total laryngectomy used to be the preferred surgery for high-grade, extensive tumors, those affecting more than 50% of the cricoid cartilage and recurrences. The results of this systematic review reflect that survival is lower in patients in which a total laryngectomy was performed in comparison with those who underwent more conservative techniques. This may have an explanation, because patients with poor prognosis (larger, dedifferentiated, and recurrent tumours) are those in which laryngectomy was performed.

The role of chemotherapy for these tumours is negligible ^20,21. Radiation therapy has been proposed to reduce tumour volume, as adjuvant therapy in some cases of residual tumours or in non-operable patients ^6,11,22-24. Cervical metastases of CS are rare, and neck dissection should be performed only if radiological or clinical evidence of disease is present ^25-27. In this review, some authors reported neck dissection when pathological lymph node was present, as well as thyroidectomy when needed ^{20,26-31,32-34}.

Distant metastases are infrequent, and usually involve the lungs ^24,27,35-37. Tumour recurrence is common. The results of this systematic review found recurrence in 16% of cases. This fact makes close follow-up of patients mandatory, especially in those treated with conservative techniques.

The most debatable issue, to date, is what type of surgical technique is the most appropriate for LCS. Total laryngectomy should be the choice for large tumours or those with high grade or undifferentiated histology. On the other hand, conservative techniques have the main advantage of being less aggressive, but with a high risk of recurrence. This strategy may be useful for patients with a more favourable anatomy, low grade histology, or elderly patients in whom life expectancy makes tumour recurrence less likely. Close follow-up and regular monitoring is needed in these patients and in case of relapse, more aggressive techniques will be needed. Brandwein et al. ³⁸ state that given the behaviour of LCS, initial management should encompass conservative techniques. Salvage total laryngectomy in case of recurrence would be the option, without compromising survival.

Iandelli et al. ³⁹ proposed a conservative approach rather than total laryngectomy for stage III-IV non squamous cell carcinomas, including LCS. They report the use of “crico-tracheal resection and anastomosis”, “transoral laser microsurgery” and “laryngofissure” for the treatment of 8 LCS, with good results, and non-compromising survival. They proposed a decision-making algorithm that advocates laser excision or open conservative surgery in early tumour stages or in intermediate- advanced tumours with minimal involvement of the cartilage or well-differentiated histology.

The limitations of this systematic review were the heterogeneity in data reporting, primary and secondary outcomes, and follow-up. Most of the included studies are case reports or small case series. There was a lack of detailed information and clinical information in different series were unavailable or inaccurate. This fact means that some series had to be excluded from our systematic review ^40-46 despite the high number of cases reported.

Conclusions

LCS are rare tumours with good prognosis, but with a high rate of recurrence. Survival seems to be influenced by histological grade and treatment. Surgery is the treatment of choice and different approaches have been proposed. Even though there are no clinical guidelines that standardise the treatment of LCS, there is consensus among surgeons that treatment should be conservative, trying to maintain laryngeal function whenever possible. Radical nonfunctional techniques like total laryngectomy should be the option in non-favourable cases, or in recurrences.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

Conceptualisation: OA-C-I; data curation: AILP; formal analysis: MPS; investigation: RH-R; methodology: CC-P; Supervision: O-C-I; writing-review and editing: MPS and CC-P.

Ethical consideration

This study was sent to the Ethics Committee of Clinical Research of Galicia (Spain), which stated that ethical approval was not required.

Figures and tables

Figure 1.Flow chart of the systematic review.

Figure 2.Survival outcomes according to histological differentiation.

Figure 3.Survival outcomes according to surgical treatment.

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