Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer

Hypopharyngeal cancer represents approximately 7% of all cancers of the upper aerodigestive tract. More than 95% of these cancers are squamous cell carcinomas [1]. Among head and neck cancers, hypopharyngeal squamous cell carcinoma (HPSCC) is known to have the worst prognosis. In one literature, 5-year survival rates for stage III and IV HPSCC have been reported to be 36% and 24%, respectively [2]. A relatively poor prognosis and frequently advanced stage at diagnosis are due to the relative lack of symptoms for early-stage of this disease at this region.

Treatment for HPSCC remains controversial. Some authors advocate for the use of primary radiotherapy alone or in combination with chemotherapy for HPSCC [3‐6]. However, treatment of T4a HPSCC continues to fuel debate. Because HPSCC is a relatively rare disease, optimal initial treatment for T4a HPSCC has not been evaluated in any large, prospective, randomized study. Patients exhibiting cartilage invasion have poorer survival outcomes after irradiation. Therefore, T4a HPSCC with thyroid cartilage invasion is considered a distinct subcategory [7]. Clinical practice guidelines recommend upfront hypopharyngectomy with adjuvant radiotherapy for T4a HPSCC because rates of successful salvage surgery after failure of nonsurgical treatment are low [8]. The objective of this study was to present treatment results of primary surgery and identify possible prognostic factors affecting treatment outcomes in patients with T4a HPSCC.

Patients with pathologically confirmed HPSCC were recruited from six general hospitals for this multicenter study organized by a research committee of the Korea Society of Thyroid Head and Neck Surgery. Data for the following clinicopathological parameters in patients with T4a HPSCC who underwent primary surgery between 2005 and 2015 were collected: age, gender, comorbidities, tumor site and stage, postoperative treatment, pathologic specimen analysis, tumor recurrence, death, and cause of death. Tumor stage was determined based on the 2009 American Joint Committee on Cancer TNM classification. Data for a total of 416 patients with T4a HPSCC who underwent primary surgery over the 11-year period (2005 to 2015) were collected from the six centers. Among these patients, 323 were excluded because they received chemoradiotherapy for primary treatment or had recurrence of the primary tumor. Finally, a total of 93 patients were included in the study. Their mean follow-up period was 26.1 months (range, 1–118 months). Those who had positive or close margins and those with advanced T stage, lymphovascular invasion, perineural invasion, multiple nodal metastases, or extracapsular spread received additional treatment.

HPSCC is known to have poor prognosis among head and neck cancers. It is mostly found at advanced stage [9]. In the past, radical ablative surgery was conducted in hypopharyngeal cancer patients. It resulted in loss of speech and swallowing dysfunction. Total laryngectomy was introduced by Billroth et al. in 1873. It has been used as the main surgical choice for a few decades [3‐5]. With development of surgical techniques, many types of conservation surgeries have enabled surgeons to restore the function of the larynx for patients. From 1990s, chemoradiotherapy has been widely used as an alternative option for radical surgery in HPSCC. Some authors have reported that advanced chemoradiotherapy technique can provide outcome equivalent to primary surgery, even in patients with advanced stage HPSCC [6, 7]. However, for patients with advanced stage HPSCC, oncologic outcomes of chemoradiotherapy are generally inferior to those of primary surgery [4‐6]. Especially, patients with cartilage invasion have poor oncologic outcomes when they are treated with radiotherapy [7, 10]. Advanced-stage tumors with bone and cartilage invasion might harbor a hypoxic microenvironment that causes resistance to radiotherapy [11]. Recently, Scherl et al. have reported that prognosis of patients with advanced hypopharyngeal and laryngeal cancer after chemoradiotherapy is worse than that after primary surgery [12]. They concluded that proper selection of treatment modality could increase their survival rate. They also reported that 5-year DSS in the primary surgery group was significant higher than that in the chemoradiotherapy group which showed soft tissue invasion and cartilage invasion (5-year DSS: 51.1% in the primary surgery group vs. 28.5% in the chemoradiotherapy group, p < 0.05) [12].

In our series, extracapsular spread was significantly associated with rates of recurrence and survival on multivariate analysis. Many studies have reported that extracapsular spread is an indicator of poor prognosis of patients with HPSCC. Prim et al. have analyzed data of 128 patients with laryngeal and hypopharyngeal cancer and found that 3-year survival rate in patients without extracapsular spread is significantly higher than that in patients with extracapsular spread (73.4% vs. 28.9%, p < 0.001) [13]. Brasilino has analyzed data of 170 patients with laryngeal and hypopharyngeal cancer and reported that 5-year DFS of patients without cervical metastases is significantly higher than that in patients with macroscopic extracapsular spread (56.8% vs. 10.2%, p < 0.0001) [14]. In the aspect of distant metastasis, extracapsular spread has a negative effect on prognosis. According to Vaidya et al., in patients who underwent surgical resection, majority of them (18 out of 24 patients) showed recurrences for those who had cervical metastases with extracapsular nodal spread involving distant sites, especially to the lung [15].

Another significant indicator of recurrence in this study was margin status. It is known that inadequate resection can lead to increased likelihood of disease recurrence and poorer odds of survival for patients [16‐18]. Ravasz has shown that locoregional recurrence observed in 20% of 80 head and neck cancer patients is correlated with tumor positive margins [18]. In our series, involved margins were found in 29% of cases. Five-year DFS of patients with negative margins was 48% and that of patients with positive margins was 0% (p < 0.001).

Esophageal invasion was identified as an another negative prognostic factor in our study. It is well-known that patients with advanced cancer simultaneously involving the hypopharynx and cervical esophagus have very poor prognosis. Five-year survival of these patients is approximately 20–30% [19]. Wang et al. have reported about survival and complication rates of patients who have cancer involvement of both hypopharynx and cervical esophagus [3]. They have explained the reason for such difference as follows: (1) Cervical esophagus has abundant lymphatics in the submucosa and the muscularis mucosa; (2) Cervical esophageal cancer is associated with a higher rate of mediastinal lymph node metastasis than hypopharyngeal cancer [20, 21]; and (3) Carcinoma of the cervical esophagus frequently invades into the posterior membranous portion of the trachea. These reasons and theories could be used to explain results of our study showing that HPSCC with esophageal invasion showed poor outcomes in terms of DSS.

This study has several limitations. First, the number of patients was relatively small. However, HPSCC is quite rare among head and neck cancers and most patients are diagnosed in very advanced stage. Therefore, data collection was the most difficult part of such study. This was why we used a multi-center study design initially. The second limitation of this study was its retrospective nature. Despite these limitations, our study provided an important guide for treatment of T4a HPSCC and suggested prognostic factors for outcomes of surgical treatment. Lastly, patients with HPSCC who were treated by different modalities were not included.

The current study is the largest and the most robust analysis to identify specific prognostic factors in patients with T4a HPSCC treated by primary surgery. Margin involvement and extracapsular spread were significantly related to recurrence. Extracapsular spread and esophageal invasion had negative effects on survival. Such information can be used in patient counseling and appropriate risk stratification. In addition, these factors might be useful as markers to predict recurrence and prognosis of patients with T4a HPSCC.