Introduction

Laryngeal verrucous squamous cell carcinoma (LVSCC) is a distinct pathologic and clinical variant of well-differentiated squamous cell carcinoma and accounts for 1–3.4% of malignancies of the larynx [1, 2]. The larynx is the most common site within the respiratory tract and the second most common site in the body after the oral cavity [3]. LVSCC usually develops in white men (90%) in their late 60s who have a history of heavy smoking, and most commonly (80%) affects the glottic portion of the larynx [1]. Histologic confirmation of LVSCC is often difficult and requires multiple biopsies, which can significantly delay diagnosis [2]. At diagnosis, 80% of tumors are classified as T1 or T2 [1]. Cervical and distant metastases have not been reported in true cases of verrucous squamous cell carcinoma. Enlarged lymph nodes are uncommon in these patients, and only reactive changes are expected on histologic examination, so elective treatment in the neck is not warranted [2]. However, cases of hybrid verrucous carcinoma in which foci of squamous cell carcinoma are found on histopathologic examination must be treated as aggressively as conventional squamous cell carcinoma. This includes elective treatments such as neck dissection or postoperative chemo-radiotherapy (RT) once the full pathologic features of the primary tumor are known. In addition, patients with verrucous carcinoma tend to develop a second malignant tumor either in the upper airway or elsewhere due to their close association with smoking, necessitating strict follow-up after treatment of the first tumor [1, 2, 4].

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Treatment Options

As with other cancers of the larynx, treatment of LVSCC aims to eliminate the tumor while preserving the larynx and its function. Survival rates for LVSCC compare more favorably to other laryngeal cancers: in the large cohort study by Dubal et al. [1], the disease-specific survival (DSS) at 5 years for the two tumor populations was reported to be 88% and 64.4%, respectively. The most common initial treatment for LVSCC is surgery in approximately 80% of cases, followed by radiotherapy or a combination of both modalities to a much lesser extent [1, 4,5,6].

As previously mentioned, up to 80% of LVSCC cases are diagnosed as early-stage tumors (T1–T2) and without regional or distant metastases, for which limited surgery is possible, effectively removing the tumor and preserving the larynx. Using the National Cancer Database (NCDB), which records approximately 70% of newly diagnosed malignancies in the United States each year, Jayakrishnan identified 286 patients with stage Tis–T2 LVSCC who underwent primary surgery between 2004 and 2015: 76% underwent stripping or ablation, while the remainder underwent partial resection and only 3% underwent total laryngectomy [7]. Surgery ensures a high rate of local disease control regardless of stage. Echanique et al., who summarized case reports and case series of LVSCC, reported local recurrence in only 11.7% of 282 patients. A total of 78.4% of patients were treated primarily with surgery, either alone (72.3%) or in combination with other treatment modalities (6.1%) [4].

In contrast, radiotherapy appears to be less effective in controlling the disease locally. Dubal et al. conducted a population-based study of 516 patients with LVSCC and found that patients who underwent surgery alone achieved a 5-year DSS rate of 92%, which was significantly higher than 86% for those who received multimodal therapy (surgery and radiotherapy) or 76% after RT alone [1]. A similar conclusion was reached by Echanique et al., who documented 87%, 68% and 67% disease-free patients after surgery alone, radiotherapy alone and a combination of surgery and radiotherapy, respectively [4]. Furthermore, Huang et al. found 20 local recurrences (32.3%) and one regional recurrence in a series of 62 patients with LVSCC treated primarily with radiotherapy [8]. The resulting 5-year DSS, overall survival (OS) and laryngeal preservation rates of 87%, 97% and 81%, respectively, suggest that effective (limited) salvage surgery is still possible after unsuccessful radiotherapy. This is supported by large population studies that have found no differences in DSS and OS between those treated with primary surgery or primary radiotherapy, at least in patients with early-stage LVSCC [5, 9]. Obviously, surgical salvage after unsuccessful radiotherapy could contribute significantly to achieving very high cure rates for these tumors.

The role of radiotherapy in the treatment of LVSCC has been burdened in the past by the "myth" of possible anaplastic transformation of the tumor after radiotherapy. This contributes to the much higher rate of surgical treatment in patients with LVSCC than patients with other squamous cell carcinoma variants of the larynx [1]. However, it is a fact that the phenomenon of anaplastic transformation of verrucous squamous cell carcinoma after radiotherapy, often emphasized in the older literature, is overestimated in its frequency [10, 11] and is questionable in the context of more recent data. For example, Huang et al. did not find a single case of anaplastic transformation in 62 patients with a median follow-up of 11 years [8]. Less differentiated tumors that occur after previous radiation of a verrucous carcinoma are more likely to be expanding foci of conventional squamous cell carcinoma that were missed on initial biopsy [12]. Another issue related to radiotherapy is the significant advances in radiation technology that allow for more precise and effective eradication of tumors. The same applies to the understanding of radiobiological factors, which also have considerable influence on the effectiveness of radiotherapy. Understanding the relationship between the cytokinetic properties of tumors and overall treatment time, which has led to the development of moderately hypofractionated radiation regimens that are now standard for early-stage glottic carcinomas, is particularly important for well-differentiated tumors such as verrucous squamous cell carcinoma [13]. For these reasons, current and past radiotherapy practices are by no means comparable as they can lead to different clinical outcomes [14]. The third important factor to consider when evaluating the outcomes of radiotherapy versus surgery is the likely selection bias that cannot be detected and eliminated in retrospective studies and population-based cohort studies. As with other cancers, patients who are less suitable (or unsuitable) for surgical treatment due to anatomical features, tumor size or comorbidities are more likely to be referred for radiotherapy.

Even less is known about the role of chemotherapy in the treatment of LVSCC. In a systematic review of the literature, Echanique recorded only seven cases treated with chemotherapy [4]. The largest group of four patients was reported by Strojan et al.: all were treated with concurrent radiotherapy and combined chemotherapy with vinblastine, methotrexate and bleomycin [2]. Despite the advanced tumors for which total laryngectomy was the only option, all patients were tumor-free at last follow-up, ranging from 3.2 to 13.6 years (median 8.1 years) after completion of treatment. The same authors also reported on seven patients with a head and neck verrucous carcinoma outside the larynx who were successfully treated in the same way [15]. There are isolated but positive reports in the literature on the use of chemotherapy alongside radiotherapy or as a primary treatment modality, often with intra-arterial administration, for verrucous carcinoma in the oral cavity [16].

Conclusions

The existing literature suggests that the preferred treatment modality for early-stage LVSCC is endoscopic surgery, which offers superior local control and functional preservation of the larynx. More extensive and mutilating surgery should be reserved for advanced tumors and salvage when functional preservation of the larynx is not possible. In view of the good rescue options and the DSS, OS and laryngeal preservation rates comparable to primary surgery, radiotherapy is also a viable option for older and polymorbid patients. However, it must be carried out according to modern technical and radiobiological principles. Given the current data refuting the possibility of negative effects of radiotherapy on the natural history of LVSCC, the phenomenon of anaplastic transformation should not discourage the use of radiotherapy for LVSCC when indicated. The role of chemotherapy and other modern systemic therapies, either as stand-alone modalities or in combination with radiotherapy, in the context of larynx-preserving treatments for LVSCC should be further investigated.