Verrucous carcinoma is a rare variant of squamous cell carcinoma. It was first reported as an exogenous and well-differentiated variant by Ackerman in 1948. The oral cavity, genitals, larynx, esophagus, and skin are usually involved, and the head and neck regions are the most affected areas. It grows slowly, mainly exogenously, and can reach a considerable extent before the patients notice it. It looks like a papillary mass with a grayish-white or red color, which is different from the typical ulcer nodule characteristics of squamous cell tumors. Histologically, verrucous carcinoma shows severe keratinization, well-differentiated, and lack of atypia. It has only local invasiveness and little metastatic potential.[3,4]
Verrucous cancer mainly affects the mouth and throat in the head and neck. It is mainly found in older men, usually around the age of sixty, and is closely related to the use of tobacco and areca.[5,6] Surgery is still the primary treatment, radiotherapy, and chemotherapy as adjuvant therapy.[7–9]
Although there are some studies on head and neck squamous cell carcinoma in the literature,[10–12] there is no extensive population-based analysis of head and neck verrucous cancer. Because this type of tumor is very rare, only a few case reports describe the epidemiology and relevant factors that influence survival outcomes.[13–15] Therefore, we decided to use population-based data to further investigate the incidence, treatment, and survival of head and neck verrucous carcinoma.
2 Materials and methods
2.1 Data extraction and management
We used VC and OHNM cases from the SEER database (1973–2015) for analysis. Since the patients’ information is anonymous, and all data comes from the SEER public database, an additional approval from the ethics committee or institutional review board is not necessary. Using the topography codes (C00-C14; C30-C33; C41.0; C41.1; C44.0–4; C47.0; C49.0; C76.0 and C77.0), we identified the malignancies happened in head and neck. The historical type code (8051/3) of the International Classification of Diseases for Oncology, third edition (ICD-O-3), was used to retrieve the VCs’ data. By combining the topography codes with the historical type code, we extracted data of head and neck VC patients. In the meantime, we extracted data from all head and neck malignancies without a historical type code of 8051/3 as the ONHMs group. We excluded patients using the following criteria:
- (1) VC was not the first tumor;
- (2) lacking histology confirmation;
- (3) missing essential information.
The patient demographics, clinical characteristics, follow-up, and vital status, were acquired using SEER∗Stat software (version 8.3.4; National Cancer Institute, Bethesda, MD). We set cancer-specific survival (CSS) and overall survival (OS) as the endpoints.
2.2 Statistical analysis
For baseline characteristics, continuous variables were described by means and standard deviations and compared using the t test. Categorical variables were described using frequencies and percentages and compared using the Chi-square test or Fisher exact test. We used propensity score matching (1-to-1) method to mimic randomized controlled trials and reduce the selection bias. Nearest-neighbor matching was performed with a stringent caliper of 0.02, and age and sex were selected into the logistic regression model. The survival period was calculated from the date of the VC diagnosis until the time of death or the last follow-up. The survival analysis was conducted using the Kaplan–Meier method with the log-rank test. We conducted all the analysis using SPSS, version 24.0 (SPSS Inc., Chicago, IL). A Two-sided P < .05 was considered statistically significant.
In our study, 2039 VC patients and 394,739 patients with other head and neck malignancies (OHNMs) between 1973 and 2015 from the SEER database were extracted. The demographic characteristics are shown in Table 1. Patients with VC were older than patients with OHNMs (median age: 67 vs 62 years, P < .001). Compared with OHNMs, more VC cases were found in females (36.6% vs 31.1%; P < .001) and had a smaller tumor size (P < .001). The tumors of VC patients had a lower histological grade and SEER stage than OHNMs’ (both P < .001). Besides, there was no significant difference in gender between both groups. As shown in Figure 1, VC patients (green line) had a better cancer-specific survival rate compared with the OHNM patients (Fig. 1A, P < .001). For the overall survival, survival for VC seems to be better, up to about 200 months, and gets worse subsequently (Fig. 1B, P < .001).
3.2 Tumor characteristics of VCs
As shown in Table 2, we summarized the TNM and American Joint Committee on Cancer (AJCC) seventh stages of VCs (year 2010+, n = 445). For these patients, T1 was the most common stage (39.8%), followed by T2 (22.9%), T3 (6.7%), and T4 (5.6%). The 84.9% of VC patients had no lymph node involvement, and no patients had distant metastasis. About AJCC staging, the fractions were decreased corresponding to the stages from high to low: I (37.5%), II (21.1%), III (8.3%) and IV (6.5%).
3.3 Incidence exploration
After age adjustment to the 2000 US Standard Population, the incident rate of VC was 0.075 per 100,000 between 2000 and 2015 (Table 1). It is different from the relatively stable incidence of OHNMs (0.033 per 100,000, P = .413), where the incidence rate of VC was decreasing (Fig. 2). The annual percentage change of the incidence was −1.855 (P < .001).
3.4 The relationship between different therapies and VC patients’ survival
The treatments for VCs and OHNMs were shown in Table 3. Most VC patients had conducted surgical treatments (51.3%), a statistical difference compared with the OHNM cohort (41.0%, P < .001). Patients with OHNMs had undergone more frequent chemotherapy, radiotherapy, and a combination of multiple treatments compared to the VC patients (27.2% vs 4.1%; 48.3% vs 21.0%; 5.8% vs 1.4%, all P < .001).
The Kaplan–Meier analysis was used to evaluate the effectiveness of different therapies in VC patients. As Figure 3 showed, both for OS and CSS, surgical treatment exhibited an excellent therapeutic effect (P < .001). However, the prognosis for VC patients given chemotherapy and radiotherapy was worse than the ones who did not.
What is more, we made a comparison among three treatment modalities, including surgery alone, chemotherapy alone, radiotherapy alone, combined surgery with chemotherapy, and combined surgery with radiotherapy (Fig. 4). The overall survival and cancer-specific survival exhibit the same trend. The result showed that surgical treatment could effectively prolong the patients’ prognosis. A combination of a variety of treatments based on surgical treatments may improve the patient's prognosis.
Although there are a small number of epidemiological studies on laryngeal squamous cell carcinoma, similar studies of head and neck verrucous carcinoma are still lacking. Head and neck verrucous cancer usually occurs in the mouth, but there are some cases reported that can occur in the throat and sinuses. It looks like a cauliflower in morphology. Under the microscope, it is composed of a thick, well-differentiated keratinized squamous epithelium that lacks cytological atypia. At the matrix interface, it always has a clear push boundary, so it is difficult to assess its invasiveness. It grows slowly compared to other head and neck malignancies. Although it can cause local damage, studies have shown that it is unlikely to transfer, which is the same as our result. Therefore, in order to have a better understanding of head and neck verrucous cancer, we compared the incidences and survival rates between head and neck verrucous cancer and other malignant tumors of the head and neck in this study.
We found that the cancer-related survival rate and overall survival rate of head and neck squamous cell carcinoma were better than other malignant tumors of the head and neck, but the difference became less evident for the long-term survival. Although the head and neck verrucous cancer itself grows slowly and has rare metastasis, in the long term, it may cause harmful long-term effects to the body. According to our data, the incidence of head and neck verrucous cancer decreased in the recent years, which was different from other malignant tumors in the head and neck. This downward trend may be caused by the improved detection techniques, which makes it easier to identify head and neck verrucous cancer from other head and neck malignant tumors. In the old days, we distinguished them through the tumor morphology and pathological morphology. This process makes us misdiagnose easily because of human error. Now, we can use separate biomarkers, such as CK10 and CD68, or do deep biopsies, for example. These procedures are much more accurate than before.[23,24] The trend might also be caused by the discovery about the harm of tobacco and areca in recent years, which reduces the incidence of verrucous cancer of the head and neck.
At present, the main treatment methods for head and neck verrucous cancer include surgery, radiotherapy, and chemotherapy.[20,25] Surgical treatment has been the primary therapeutic method for verrucous cancer. It is no doubt that there would be a dysfunction after an oral tumor resection, and some patients cannot afford surgical treatment because of their poor body condition. Therefore, a small number of patients choose to conduct radiotherapy or chemotherapy. There are few types of research which have been conducted to compare the effects of these treatments in head and neck verrucous cancer. We firstly compared the cancer-specific survival rate and the overall survival rate between the patients with or without these three treatments. We found that patients with surgical treatment had a better prognosis than patients without surgery. Their cancer-related survival rate and overall survival rate were higher than patients who had not been operated. However, in general, patients with radiation therapy had a worse prognosis than patients without radiotherapy. Moreover, patients with chemotherapy had a worse prognosis than patients without chemotherapy. Their survival rate was lower than those without radiotherapy or chemotherapy. These results indicated that the therapeutic effect of the operation was substantial, but the effect of chemotherapy and radiotherapy was not confirmed, which might be caused by the differences in the patients’ disease status. Chemotherapy and radiotherapy also have adverse effects on the physical condition of the patients. We analyzed the results of receiving these three treatments alone and different combinations of treatments. By comparing the survival data, we found that patients who only had surgical treatment had a better prognosis than patients who had undergone both surgery and radiotherapy, and at the same time, patients with surgery and radiotherapy had a better prognosis than those who received radiotherapy alone. We speculated that this might be because patients who only received radiotherapy had a higher tumor severity or sparse staging, or because radiotherapy itself was not effective. Moreover, it was shown that patients with surgery alone had a better prognosis than patients with chemotherapy alone, but patients who received surgery alone had a little difference in prognosis with patients who had undergone both surgery and chemotherapy. Patients with surgery alone had a higher cancer-specific survival rate than patients with both surgery and radiotherapy, and chemotherapy but had a little difference in overall survival. All of these suggest that when treating head and neck verrucous cancer, surgery is the best therapeutic method while radiotherapy and chemotherapy should be carefully selected, and may be of no use.
There are several limitations to our study. First, the study was a retrospective research. Second, the treatment information provided by the SEER database is not comprehensive, and it does not contain specific information on neoadjuvant therapy, postoperative adjuvant therapy, and radiotherapy. What is more, the study period spans in a long time, from 1973 to 2015. Many changes happened in diagnosis, treatment, and surveillance of VC over this period, which would bring heterogeneity. Despite these limitations, our study provides a large cohort of VC patients and illustrates essential clinical information about VCs.
VC is rare and less aggressive than OHNM. Surgical treatments can significantly prolong VC patients’ prognosis.
Conceptualization: Ming Huang, Hong Lv.
Data curation: Na Wang.
Formal analysis: Na Wang.
Investigation: Na Wang, Ming Huang.
Methodology: Na Wang, Ming Huang.
Project administration: Na Wang, Ming Huang.
Supervision: Ming Huang, Hong Lv.
Visualization: Ming Huang.
Writing – original draft: Na Wang, Hong Lv.
Writing – review & editing: Hong Lv.
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