Primary subglottic Squamous Cell Carcinoma (SCC) is a rare malignancy accounting for only 1%–3% of all laryngeal carcinomas.1–3 It is generally asymptomatic at earlier stages and typically presents at advanced stages, leading to substantially worse prognosis than Laryngeal Squamous Cell Carcinomas (LSCCs) originated from supraglottic and glottic.3,4 Despite recent progress in treatment of laryngeal carcinoma, no consensus on the optimal subglottic SCC management has been reached.5 The therapeutic strategy varies depending on the stage of disease, which usually containing surgery, adjuvant therapy, or a combination of both. Mounting evidence suggests that early-stage subglottic SCCs can be managed with a single type of treatment, whereas advanced-stage tumors require combined-modality therapy.6–8 Although radiotherapy preserves laryngeal function, its ability to improve long-term patient survival remains controversial.9–11 Chemotherapies, including induction Chemotherapy and Concurrent Chemoradiotherapy (CCRT), are widely used to treat laryngeal carcinoma; however, their clinical usefulness in patients with subglottic SCC remains unclear.12–14 In this study, we conducted a retrospective analysis using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to investigate the demographic and clinicopathological characteristics as well as survival outcomes of subglottic SCC.

Subglottic SCC is a rare entity accounting for less than 5% of all LSCC.15–17 We acquired data of LSCC between 1996 and 2016 since meticulous records were just starting to be collected into the SEER database in recent decades, not to mention the rapidly development of management towards laryngeal carcinoma. We confirmed the rarity of subglottic SCC: a total of 48,521 laryngeal SCC cases were registered, with only 842 (1.7%) subglottic SCC cases. Most studies on subglottic SCC involved small cohorts for its rarity, making it difficult to establish the incidence and the underlying mechanisms.18 The imprecise definition of the superior subglottic border, accidental sampling of subglottic-invading glottic SCC, and undetermined origins of advanced-stage disease further challenge the elucidation of the clinicopathological characteristics of subglottic SCC.19,20

Numerous studies have shown that men are more susceptible to LSCC than women due to the much commonly exposures to environmental risk factors, for instance tobacco.21,22 Consistently, we found subglottic SCC is more frequent among white males aged 60–70 years, and those at advanced age suffered unfavorable overall survival outcomes.4,7,16 The average tumor size was 28.76 mm in current study. Considering these data may have been derived from surgical specimens, they might not to be representative of actual tumor size; but we still verified that larger tumor is independent risk factor for both OS and CSS, which reinforced the notoriously consensus that local staging of LSCC is proportional to tumor size.23 Although high-grade lesion was found in only 22.1% cases, it did have a devastating effect on CSS. Admittedly, pathological staging represents important information and should be included in staging, it doesn’t supplant clinical staging as the primary scheme yet.24 Among patients with available clinical information, most of whom were at advanced stage which were primarily due to T4 disease, reflected by 18.1% patients presented cervical lymphatic involvement. Our results agreed with the prevailing studies as despite the locally advanced invasion at presentation, subglottic SCCs may infrequently present with cervical lymphatic involvement with reported incidences ranged from 4% to 21.5%.3,25–27 Subglottic SCCs prone to escape through the intercartilagenous infrastructure rather than invading across the cartilaginous boundaries of larynx, result in disease progression without overt early symptoms and missed diagnosis during imaging examination.4 Subsequent analysis of risk factors confirmed the independently predictive effects of tumor invasion extent and LNM extent, which directly related to the staging and prognosis of LSCC.5,16 The lymphatic drainage pathway of the subglottis starts from prelaryngeal (Delphian) or pretracheal lymph nodes to paralaryngeal or paratracheal then crosses the midline, allowing for metastases through-out level VI to the lateral neck, and higher prevalence of LNM could lead to impaired survival.20,28 Our finding validated these studies as the higher the positive ratio of metastatic lymph nodes, the worse the OS and CSS rates. However due to incomprehensive distribution of data, deeply exploration of survival outcomes with certain-area invasion, for example cricoid cartilage and prelaryngeal/paralaryngeal lymph nodes where subglottic LSCCs were reported easier to infringe, was unable to carry out.29,30 Unfortunately, this research attempted but failed to investigate if the neurovascular invasion or extranodal extension had associations with poor prognosis in subglottic SCC because of data missing in the SEER database.

The aggressive behaviors of subglottic SCC are featured as predilection for laryngotracheal cartilage, extra-laryngeal invasion, high incidence of paratracheal nodal metastasis, and propensity for stomal recurrence, as a result the prognosis of patients is always extremely unfavorable.2,25 In this study, we confirmed the low 5-year OS and CSS rates of patients with subglottic SCC. Notably, patients with high-grade tumors or advanced-stage disease had significantly worse survival outcomes, suggesting that clinical stage and histologic grade are important factors predicting the long-term survival of patients with subglottic SCC. Interestingly, the prognosis of subglottic SCC remained similar over the past few decades, despite the progress in cancer treatment; however, it varied markedly over the past decades based on the treatment modality as reported, which possibly due to the differences in cohort sizes.4,11,14,25,31

Patients with early-stage subglottic SCCs are often treated with a single treatment modality, whereas those at advanced-stage require a combination of multimodalities.9,16,32,33 Starting with the landmark Veterans Affairs (VA) larynx trail, organ preservation protocols are increasingly being used for the treatment of laryngeal SCC.34 Thus, personalized and stratified treatment can occur in an organic and experimental fashion where patients can be shifted to appropriate regimens depending on their response to the therapy.35,36 In light of its rarity, it has been difficult to draw conclusions on survival based upon treatment modality for subglottic SCC. Although non-surgical treatments were performed much frequently, we confirmed that surgery-oriented therapies, especially for the combination of surgery and radiotherapy, provided much favorable survival outcomes which lend credence to the conclusions proffered by Shi et al. as well.27 Few researches have focused on the application of chemotherapy on subglottic SCC regardless of its promising effects. We preliminary analyzed the survival outcomes of subglottic SCC treated with chemotherapy: the single use of chemotherapy or surgery plus chemotherapy failed to provide better survival outcomes which may attribute to insufficient distribution of cases in these regimens; while chemotherapy revealed positive effects to patients’ overall survival when combined with surgery or radiotherapy. CCRT has been verified to be of great help for preservation of larynx function, but we were unable to analyze its effect due to lack of specific data of chemotherapy and radiotherapy in SEER.37 Together, these findings demonstrate that the management of subglottic SCC can be highly variable and further studies would shed a light on the usefulness of multiple treatment regimens for subglottic SCC.

Currently, most patients with locally advanced subglottic SCC undergo a total laryngectomy, usually combined with neck dissection and, if necessary, thyroidectomy. Larynx preservation surgery is preferred for patients with early-stage subglottic SCC. Shaha et al. first reported long-term survival of early-stage subglottic SCC patients treated with organ preservation surgery, which was confirmed by another recent study as preservative laryngectomy provided up to 80% of 5-year disease-free for early-stage subglottic SCC.7,23 Nevertheless, patients with advanced stage disease didn’t do well with organ-preservation therapies.34 In current study, patients who underwent total laryngectomy had the worst survival outcomes; by contrast, larynx preservation surgeries provided much favorable results. Further analysis between total laryngectomy and local tumor excision confirmed our findings after trimmed off partial laryngectomy subgroup (with only 25-cases) and adjusted for age and T staging that significantly influence the selection of surgeries for primary tumor, as well. These findings could be attributed to the fact that much patients treated with total laryngectomy had advanced-stage disease, yet larynx preservation surgeries were most commonly performed on patients at early-stage. The exacerbation of subglottic SCCs, for example advanced-stage and high-grade tumors, would eventually lead to less beneficial results from organ-preservation surgeries. It is still lack of further validation as to which type of surgery is much beneficial for the long-term prognosis since not only disease condition but also survival quality should be considered when caring patients with subglottic SCC. Of note, it was not until the middle 1990s that the efficacy of adjuvant therapy in advanced-stage laryngeal carcinoma was initially identified and accepted.38,39 In this study, patients trended towards improved survival when received both surgery and adjuvant therapy, though without statistically differences. Conversely, Santoro et al. and Garas et al. uncovered a superior effect of surgery with adjuvant therapy in their single-institution reviews of subglottic SCC, respectively.3,9 These discrepancies may have resulted from the distribution of treatment modality within the cohort, current findings may add to accumulating evidence that subglottic SCC patients would benefit from multimodality regimens, especially for advanced-stage cases. Taken together, our findings appear to corroborate previous discoveries with respect to the role for multimodality management of subglottic SCC with surgery and adjuvant therapy.

This study has several limitations: possible data errors and sampling errors may have been introduced due to the incomplete clinicopathological information and differences of case distribution on part of the patients. Miscoding in SEER may obfuscate details of cases. Additionally, the development of subglottic SCC’s management in recent years may affect our results. Finally, as the SEER database is an institution-based registry but not a true survey of the US population, the generalizability of our results should be tempered; further prospective multicenter randomized research in managing this disease is needed.

In this retrospective, large cohort study, we confirmed the rarity of subglottic SCC, which was most common among males aged 60–70 years. Most patients were diagnosed with advanced-stage and low-grade disease. The prognosis of subglottic SCC remained poor in recent twenty-five years, despite the development in cancer therapies. The combination of surgery and adjuvant therapy improved the survival. Although patients with early-stage disease benefited from larynx preservation surgery, total laryngectomy provided favorable outcomes in patients with advanced lesions.

The authors declare no conflicts of interest.