HPV status in unknown primary head and neck cancer: Prognosis and treatment outcomes.

OBJECTIVES: Approximately 3% to 9% of head and neck cancer presents with a metastatic node and no identifiable primary tumor. These cases of head and neck carcinoma of unknown primary (HNCUP) present a therapeutic challenge. Therapy of this disease varies based on factors such as institutional, surgeon, and patient preference. Evidence demonstrating the outcomes associated with these therapies for HNCUP is limited, and among the available series, the tumor human papillomavirus (HPV) status is often ignored. Treatment deintensification has been proposed for a subset of these patients. We aim to evaluate the treatment-related outcomes for HPV-associated and HPV-negative HNCUP. METHODS: A retrospective study of 978 adult HNCUP diagnosed from 2010 to 2013 in the NCDB was conducted. Multivariate Cox survival regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: Patients with HPV-associated disease had superior survival, with a 3-year survival of 94.8% (standard error [SE]: 1.0), compared with 80.3% (SE: 2.9) among those with HPV-negative disease. Among HPV-negative patients with clinical nodal classification (cN)2/cN3 disease, treatment with definitive radiotherapy alone compared to definitive chemoradiotherapy was associated with diminished survival (hazard ratio 5.507, P = 0.005). Among patients with HPV-associated cancer and cN2/cN3 disease, all treatments (surgery alone, surgery with adjuvant radiotherapy, surgery with adjuvant chemoradiotherapy, definitive chemoradiotherapy, definitive radiotherapy) resulted in statistically equivalent survival. CONCLUSION: Tumor HPV status has a significant prognostic value for HNCUP and should be considered in future studies of treatment deintensification in this group. Treatment deintensification to radiotherapy alone in cN2/cN3 cases may result in poorer patient survival for HPV-negative patients, whereas it may be a promising option for further investigation in HPV-positive patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:684-691, 2019.

Adjuvant Chemotherapy Is Associated With Improved Survival for Late-Stage Salivary Squamous Cell Carcinoma.

OBJECTIVE: Salivary squamous cell carcinomas (SCCs) represent a unique disease entity because many are thought to represent metastases from primary cutaneous malignancies. Nevertheless, they represent a significant proportion of parotid gland cancers and have a notably poor prognosis. Recently, there has been controversy regarding the utility of adjuvant chemotherapy in the treatment of these malignancies, with most studies concluding that there is no survival benefit. We aim to determine the outcomes associated with the use of adjuvant radiotherapy and chemoradiotherapy in the treatment of early- and late-stage salivary SCC. METHODS: A retrospective study of 2,285 of surgically resected adult salivary SCC diagnosed from 2004 to 2014 in the National Cancer Database was conducted. Patients were divided into early- (I/II) and late-stage (III/IV) groups. Demographic, facility, tumor, and survival variables were included in the analyses. Multivariate Cox survival regressions, propensity-score matched analyses, and univariate Kaplan-Meier analyses were conducted. RESULTS: The use of adjuvant chemoradiotherapy for late-stage patients was associated with improved survival compared to the use of adjuvant radiotherapy alone (hazard ratio [HR] 0.774, P = 0.026). Five-year survival for late-stage patients treated with surgery alone, surgery with adjuvant radiotherapy, and surgery with adjuvant chemoradiotherapy was 31.1% (standard error [SE]: 2.5), 45.6% (SE: 2.2), and 58.9% (SE: 3.4). Use of adjuvant therapy (either chemoradiotherapy or radiotherapy alone) was associated with improved survival for early-stage patients (HR 0.746, P = 0.037). CONCLUSION: The addition of chemotherapy to the adjuvant therapy of late-stage patients with salivary SCC may result in improved long-term survival. Expanded use of adjuvant therapy for early-stage disease may also improve patient outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:883-889, 2019.

Treatment deintensification in human papillomavirus-positive oropharynx cancer: Outcomes from the National Cancer Data Base.

BACKGROUND: The growing epidemic of human papillomavirus-positive (HPV+) oropharyngeal cancer and the favorable prognosis of this disease etiology have led to a call for deintensified treatment for some patients with HPV+ cancers. One of the proposed methods of treatment deintensification is the avoidance of chemotherapy concurrent with definitive/adjuvant radiotherapy. To the authors' knowledge, the safety of this form of treatment de-escalation is unknown and the current literature in this area is sparse. The authors investigated outcomes after various treatment combinations stratified by American Joint Committee on Cancer (AJCC) eighth edition disease stage using patients from the National Cancer Data Base. METHODS: A retrospective study of 4443 patients with HPV+ oropharyngeal cancer in the National Cancer Data Base was conducted. Patients were stratified into AJCC eighth edition disease stage groups. Multivariate Cox regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: For patients with stage I disease, treatment with definitive radiotherapy was associated with diminished survival compared with chemoradiotherapy (hazard ratio [HR], 1.798; P = .029), surgery with adjuvant radiotherapy (HR, 2.563; P = .002), or surgery with adjuvant chemoradiotherapy (HR, 2.427; P = .001). For patients with stage II disease, compared with treatment with chemoradiotherapy, patients treated with a single-modality (either surgery [HR, 2.539; P = .009] or radiotherapy [HR, 2.200; P = .030]) were found to have poorer survival. Among patients with stage III disease, triple-modality therapy was associated with improved survival (HR, 0.518; P = .024) compared with treatment with chemoradiotherapy. CONCLUSIONS: Deintensification of treatment from chemoradiotherapy to radiotherapy or surgery alone in cases of HPV+ AJCC eighth edition stage I or stage II disease may compromise patient safety. Treatment intensification to triple-modality therapy for patients with stage III disease may improve survival in this group. Cancer 2018;124:717-26. © 2017 American Cancer Society.

Extracapsular extension is not a significant prognostic indicator in non-squamous cancers of the major salivary glands.

BACKGROUND: Extracapsular extension (ECE) is a well-established prognostic feature in squamous cell cancers of the head and neck. Although some extrapolate data from mucosal head and neck cancer to include ECE as a high-risk feature in salivary gland cancers, data is lacking about ECE's prognostic value for these malignancies. We investigate whether ECE is a significant prognostic indicator in pathologic node-positive cancers of the major salivary glands. METHODS: A retrospective study of adult salivary gland cancer cases diagnosed from 2004 to 2013 in the NCDB was conducted. Demographic, tumor, treatment, and survival variables were included in the study. Univariate Kaplan-Meier analyses, as well as multivariate Cox survival regressions were performed. RESULTS: Positive ECE status was associated with significantly worse survival in salivary SCC (HR 1.687; p = 0.002) but not non-squamous salivary cancers (HR 1.000; p = 0.998) on multivariate analysis. While post-operative radiotherapy was not associated with improved survival for patients without high-risk adverse features (high grade or positive surgical margins), its use was associated with better survival for ECE-positive salivary SCC patients without one of these additional adverse features (HR 0.064; p = 0.010). CONCLUSIONS: Although ECE is a significant prognostic indicator in salivary SCC, its prognostic significance for non-squamous salivary cancers may be limited. Radiotherapy may improve survival in cases with at least one high-risk adverse feature: high grade; positive surgical margins; and for salivary SCC specifically, positive ECE status.

Parotid gland lymphoma: prognostic analysis of 2140 patients.

OBJECTIVES/HYPOTHESIS: Assess the demographic, clinical, and pathologic features of patients with parotid gland lymphoma and their prognostic importance using US population-based data. STUDY DESIGN: Retrospective cohort study. METHODS: Patients were selected from the Surveillance, Epidemiology, and End Results program database between the years of 1973 and 2008, and individual characteristics were compared using univariate and multivariate Cox proportional hazards models. Kaplan-Meier survival curves were constructed and log-rank tests were performed. RESULTS: We identified 2,140 patients with primary parotid gland lymphoma. Hodgkin lymphoma was found in 3.5% of patients. More common were non-Hodgkin lymphoma subtypes: marginal zone B-cell lymphoma, follicular lymphoma, and diffuse large B cell lymphoma accounted for 27.9%, 25.8%, and 23.7% of cases, respectively. Survival was decreased with patient age over 50 years, increasing stage, male gender, non-Hodgkin histology, and status other than married. Of the patients, 72.0% received some form of surgery, and 136 patients had facial nerve sacrifice during parotidectomy. CONCLUSIONS: Non-Hodgkin lymphoma is the predominant type of lymphoma seen in the parotid gland. Patient and histologic features determine survival, and surgery is often performed. Facial nerve sacrifice, which is contraindicated given the systemic nature of lymphoma and the role of chemotherapy and radiation in its treatment, is reported in 6.4% of patients with parotid gland lymphoma. LEVEL OF EVIDENCE: 2b.

Use of intravenous immunoglobulin to treat chronic bilateral otomastoiditis in the setting of rituximab induced hypogammaglobulinemia.

The temporal bone may be affected by a variety of systemic pathology because the disease nature, location, and extent determine the symptoms. Middle ear and mastoid infections may be the initial clinical manifestation of autoimmune and acquired immunodeficiency disorders. Rituximab, an anti-CD20 chimeric antibody, has become increasingly popular as a therapeutic agent for patients with a wide range of autoimmune disorders refractory to standard treatments. Normal levels of immunoglobulin levels are usually maintained during and after rituximab therapy, and clinical trials to date have shown no statistically significant increase of serious infections among patients with autoimmune diseases being treated with rituximab (Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al, for the REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum. 2006;54:2793-2806. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572-2581). However, there have been several reports of opportunistic infections associated with rituximab (Kelesidis T, Daikos G, et al. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infect Dis 2011;15:e2-e16. Teichmann LL, Woenckhaus M, Vogel C, et al. Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology 2008;47:1256-1257), as well as cases of it accelerating the presentation of hypogammaglobulinemia (Diwakar L, Gorrie S, et al. Does rituximab aggravate pre-existing hypogammaglobulinaemia? J Clin Pathol 2010;63:275-277). Humoral immune defects can cause persistent acute and serous otitis media, with the development of chronic suppurative otitis media refractory to medical and surgical therapy (Sasaki CT, Askenase P, Dwyer J, et al. Chronic ear infection in the immunodeficient patient. Arch Otolaryngol 1981;107:82). Here, we describe the first presentation, diagnostic workup, and treatment with intravenous immunoglobulin of chronic bilateral otomastoiditis in the setting of rituximab-induced hypogammaglobulinemia.