Date Published: July 7, 2017
Publisher: Public Library of Science
Author(s): Yu-Han Huang, Chih-Hua Yeh, Nai-Ming Cheng, Chien-Yu Lin, Hung-Ming Wang, Sheung-Fat Ko, Cheng-Hong Toh, Tzu-Chen Yen, Chun-Ta Liao, Shu-Hang Ng, Craig Meyers.
We investigated the relationships of cystic nodal metastasis, human papillomavirus (HPV) status, and treatment failure patterns in patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with chemoradiotherapy.
We retrospectively reviewed pretreatment MRI and clinical courses of patients with OPSCC whose tumors were tested for HPV-induced p16 expression via immunohistochemistry and who completed chemoradiotherapy. Cervical cystic nodal metastasis and necrotic nodal metastasis were classified on MRI.
Of 98 patients eligible for analysis, 33 were p16-positive. Cystic nodal metastasis was significantly more prevalent in p16-positive than in p16-negative patients (39.4% versus 18.5%, respectively; p = 0.025). Necrotic nodal metastasis was significantly more prevalent in p16-negative than in p16-positive patients (73.8% versus 51.5%, respectively; p = 0.027). On multivariate analysis, necrotic nodal metastasis (odds ratio [OR] = 7.310, p = 0.011) was an independent predictor of regional failure, while advanced nodal stage (OR = 4.119, p = 0.022) and cystic nodal metastases (OR = 0.087, p = 0.026) were independent positive and negative predictors of distant failure, respectively.
Cervical cystic and necrotic nodal metastases are associated with HPV-induced p16-positive and p16-negative OPSCC, respectively. Patients with necrotic nodal metastasis at presentation have an increased risk of regional failure. Distant failure is directly and inversely correlated with advanced nodal stage and cystic nodal metastasis, respectively.
Oropharyngeal squamous cell carcinoma (OPSCC) is one of the most common types of head and neck cancer. Most patients with OPSCC have regional nodal metastasis at presentation and are generally treated with an organ-preservation approach based on chemoradiotherapy . The major risk factors for OPSCC include alcohol consumption, tobacco smoking, and human papillomavirus (HPV) infection [2,3]. HPV-related OPSCC shows a gene expression profile that is distinct from OPSCC related to tobacco or alcohol . HPV-positive patients usually have more favorable prognoses than HPV-negative patients, with superior responses to radiation and chemotherapy . HPV16/18 are the most commonly detected transcriptionally active HPV types. Immunohistochemistry for p16 overexpression has emerged as a robust surrogate biomarker for HPV-mediated carcinogenesis and as an independent positive prognosticator . Direct detection of HPV is not used as a defining factor owing to limited availability of the test, cost, and lack of advantage of over p16 overexpression in terms of predicting survival. Hence, p16 overexpression was chosen as the best identifier of disease because of its low cost, universal applicability, and ease of analysis compared to other HPV identifiers . The association between HPV status and cervical cystic nodal metastasis has been investigated in retrospective reviews of pretreatment computed tomography (CT) examinations of OPSCC [8–10]. Goldenberg et al.  classified cystic metastatic nodes and necrotic metastatic nodes on images as follows: cystic nodes were defined as those having homogeneous fluid content without internal complex, irregular, or solid areas and an enhancing capsule <2 mm in thickness, while necrotic metastatic nodes were defined as those having thicker walls and irregular, complex central low attenuation. They found that 87% of the patients (11 of 13) with cystic nodal metastases were HPV-positive; thus, they proposed that a strong association exists between cystic cervical nodal metastases and HPV-positive OPSCC. Subsequently, Cantrell et al.  and Morani et al.  used these criteria in their review of CT images of their patients with OPSCC; their results supported the existence of an association between cystic nodal metastasis and HPV-positive OPSCC. However, to our knowledge, a correlation between cystic nodal metastasis and tumor control after chemoradiotherapy in patients with OPSCC has not been reported. A total of 105 patients who were newly diagnosed with OPSCC and who met the inclusion criteria were enrolled in the study. Seven patients died before definitive treatment failure could be determined; therefore, 98 patients were available for analysis, including 89 men and 9 women with a median age of 53 years (range 33–78 years). The palatine tonsil was the most common primary tumor site, occurring in 62 patients (63.3%). All our patients had advanced stage disease based on 8th edition of American Joint Committee on Cancer staging (2017); 10 patients (10.2%) had stage I, 6 (6.1%) had stage II, 22 (22.4%) had stage III, 37 (37.8%) had stage IVa, and the remaining 23 (23.5%) had stage IVb. The clinicopathological characteristics of the 98 patients are summarized in Table 1. Of these 98 patients, 33 were p16-positive, including 28 men and 5 women with a mean age of 55.5 years. The remaining 65 patients were p16-negative, including 61 men and 4 women with a median age of 51.7 years. Comparisons of clinical and imaging characteristics relating to p16 status are presented in Table 2. No significant differences between p16-negative and p16-positive patients were found in terms of sex, age, T-stage, or N-stage. Alcohol, cigarette, and betel quid use were more prevalent in p16-negative patients than in their p16-positive counterparts. The inter-observer agreement between the two raters for both cystic nodal metastases and necrotic nodal metastasis was substantial (Cohen’s kappa for cystic nodal metastasis: k = 0.663, p<0.001; and for necrotic nodal metastasis: k = 0.780, p<0.001). Cystic nodal metastasis was significantly more prevalent in patients with p16-positive tumors than those with p16-negative tumors (39.4% versus 18.5%, p = 0.025). In contrast, necrotic nodal metastasis was significantly more prevalent in patients with p16-negative tumors than those with p16-positive tumors (73.8% versus 51.5%, p = 0.027). Although head and neck squamous cell carcinoma (HNSCC) incidences have remained stable or even declined in recent years, OPSCC rates have increased because of higher HPV infection rates . HPV-positive tumors represent a separate subset of OPSCC with a unique epidemiology; their etiologies and biologic characteristics are distinct, and they generally exhibit more favorable prognoses [2,3,5,15]. Patients with HPV-related OPSCC tend to be relatively young and are less exposed to tobacco and alcohol; these are distinguishing factors compared to patients with classic HPV-unrelated OPSCC [15,16]. In our Taiwanese study population, we found that, in addition to alcohol-drinking and tobacco-smoking, betel quid chewing was found to occur significantly more frequently among HPV-induced p16-negative patients with OPSCC compared to their p16-positive counterparts. Indeed, betel quid is claimed to be the most important contributing factor to the increasing incidence rates of OPSCC in Taiwan besides alcohol and tobacco . Our results indicate that increased rates of OPSCC due to betel quid use predominantly represent p16-negative disease. Another noteworthy clinical characteristic found in this study was the relatively older age of our p16-positive patients, with a mean of 56 years. We posit that this may be attributable, at least in part, to differences in ethnicity, lifestyle, and/or sexual behavior between Taiwanese and Western populations. Our study showed that cervical cystic metastatic nodes observed on pretreatment MRI were prevalent in p16-positive patients with OPSCC, while cervical necrotic metastatic nodes were prevalent in p16-negative patients. The presence of cervical necrotic nodal metastasis at presentation was significantly correlated with an increased risk of regional failure. The risk of distant failure increased with advanced nodal stage but decreased with cervical cystic nodal metastasis. On posttreatment follow-up, close attention ought to be paid to the neck region for patients with OPSCC who exhibit necrotic nodal metastases, as well as to distant sites in patients with advanced nodal stages but without cystic nodal metastasis. Source: http://doi.org/10.1371/journal.pone.0180779