Daniel, J.

ObjectiveFailure to recognize symptoms of non‐human papillomavirus‐associated oropharyngeal squamous cell carcinoma (HPV(−)OPSCC) at presentation can delay diagnosis and treatment. We aim to identify patient factors and provider practice patterns that delay presentation and care in HPV(−)OPSCC.MethodsRetrospective review at a tertiary care center. Patients with HPV(−)OPSCC receiving treatment from 2006 to 2016. Patients were excluded if their date of symptom onset or diagnosis was unknown after thorough review of the electronic medical record or their tissue was not tested for HPV or p16. Clinical data, workup, and care timelines were abstracted. Univariate and multivariable linear regressions were performed to determine associations between patient and provider factors and delays in care.ResultsOf 70 included patients, 52 (74%) were male and mean age was 60.5 (SD = 9.0). Median time to diagnosis was 69 days (IQR = 32–127 days), with a median latency of 30 days (IQR = 12–61 days) from symptom onset to first presentation and 19.5 days (IQR = 4–46 days) from the first presentation to diagnosis. Most patients visited at least 2 providers (n = 52, 74%) before diagnosis. Evaluation by 3 or more providers prior to diagnosis was associated with significant delays in diagnosis of nearly a year (357.7 days, p < 0.001) and being treated or prescribed analgesia prior to diagnosis was significantly associated with delays in diagnosis (p = 0.004) on univariate regression analysis.ConclusionsDelays in care related to evaluations by multiple providers and misdiagnosis prolonged time to diagnosis in HPV(−)OPSCC. Improved patient and provider education is necessary to expedite the diagnosis of HPV(−)OPSCC.Level of Evidence4 Laryngoscope, 133:1394–1401, 2023

Background and purpose Radiation therapy is an important component of treatment in patients with malignancies of the head, neck, and spine. However, radiation to these regions has well-known potential side effects, many of which can be encountered on imaging. In this manuscript, we review selected radiographic manifestations of therapeutic radiation to the head, neck, and spine that may be encountered in the practice of radiology. Methods We conducted an extensive literature review of known complications of radiation therapy in the head, neck, and spine. We excluded intracranial and pulmonary radiation effects from our search. We selected complications that had salient, recognizable imaging findings. We searched our imaging database for illustrative examples of these complications. Results Based on our initial literature search and imaging database review, we selected cases of radiation-induced tumors, radiation tissue necrosis (osteoradionecrosis and soft tissue necrosis), carotid stenosis and blowout secondary to radiation, enlarging thyroglossal duct cysts, radiation myelopathy, and radiation-induced vertebral compression fractures. Conclusions We describe the clinical and imaging features of selected sequelae of radiation therapy to the head, neck, and spine, with a focus on those with characteristic imaging findings that can be instrumental in helping to make the diagnosis. Knowledge of these entities and their imaging findings is crucial for accurate diagnosis. Not only do radiologists play a key role in early detection of these entities, but many of these entities can be misinterpreted if one is not familiar with them.

Abstract BACKGROUND Intensity‐modulated proton therapy (IMPT) demonstrates superior dose distribution over volumetric‐modulated arc therapy (VMAT) for sparing organs‐at‐risk (OARs) in ipsilateral radiotherapy. To determine a clinical benefit, assessment of patient‐reported outcomes (PRO) and physician‐reported toxicities alongside a dosimetric analysis is needed. METHODS Plans were analyzed for dosimetric differences. PROs were compared for patients undergoing ipsilateral curative‐intent radiotherapy for tonsil and salivary gland cancers with VMAT or IMPT from 2015 to 2020. Physician‐reported toxicities were compared. RESULTS In 40 patients, IMPT was associated with decreased dose to multiple OARs and less deterioration in the following PROs: pain, swallowing function, dry mouth, sticky saliva, sensory change, cough, speech, feeling ill, and social eating. Physician‐reported toxicities demonstrated less oral pain. CONCLUSION IMPT is associated with decreased dose to OARs and less patient‐reported acute deterioration in multiple head and neck domains. A strong consideration for IMPT in ipsilateral head and neck patients with cancer is warranted.

ObjectiveTo describe and compare rates of metachronous and synchronous second primaries of the contralateral tonsil in patients with primary HPV(+) tonsillar squamous cell carcinoma (SCC).Study DesignRetrospective cohort study.Materials and MethodsThis is a single tertiary care center retrospective case series, from 2006 to 2019, of HPV(+) tonsillar SCC patients who underwent primary surgical resection with unilateral wide‐field tonsillectomy or bilateral tonsillectomy for diagnostic or therapeutic purposes. A metachronous second primary is one diagnosed >6 months after completion of surgical treatment. A synchronous second primary is one diagnosed during bilateral tonsillectomy for unilateral HPV(+) tonsillar SCC. Rates of second primary and patient characteristics were compared using chi‐square tests.ResultsAbout 303 patients underwent unilateral surgical resection +/− adjuvant therapy for HPV(+) tonsillar SCC. One (0.3%) developed a metachronous second primary in the contralateral tonsil 11.9 years following treatment. Fifty‐seven patients with HPV(+) tonsillar SCC underwent bilateral tonsillectomy, and 37/57 (65%) had no clinical signs for contralateral disease. Of these, only 1/37 (2.7%) was incidentally found to have a synchronous second primary. Twenty patients underwent bilateral tonsillectomy due to clinical concern for contralateral disease. Of these, 3/20 (15%) were found to have a synchronous HPV(+) SCC in the contralateral tonsil.ConclusionsThe prevalence of metachronous second primary after appropriate treatment of HPV(+) tonsillar SCC is very low (0.3%) and so is the chance of incidentally discovering a synchronous second primary during bilateral tonsillectomy (2.7%). We do not recommend bilateral tonsillectomy as a part of the routine algorithm in the surgical management of these patients.Level of Evidence3 Laryngoscope, 132:332–338, 2022

PurposeA magnetic resonance (MR) biologic marker (biomarker) is a measurable quantitative characteristic that is an indicator of normal biological and pathogenetic processes or a response to therapeutic intervention derived from the MR imaging process. There is significant potential for MR biomarkers to facilitate personalized approaches to cancer care through more precise disease targeting by quantifying normal versus pathologic tissue function as well as toxicity to both radiation and chemotherapy. Both of which have the potential to increase the therapeutic ratio and provide earlier, more accurate monitoring of treatment response. The ongoing integration of MR into routine clinical radiation therapy (RT) planning and the development of MR guided radiation therapy systems is providing new opportunities for MR biomarkers to personalize and improve clinical outcomes. Their appropriate use, however, must be based on knowledge of the physical origin of the biomarker signal, the relationship to the underlying biological processes, and their strengths and limitations. The purpose of this report is to provide an educational resource describing MR biomarkers, the techniques used to quantify them, their strengths and weakness within the context of their application to radiation oncology so as to ensure their appropriate use and application within this field.

ObjectiveDiagnostic delay in human papillomavirus–associated oropharynx squamous cell carcinoma (HPV(+)OPSCC) is common due to nonspecific symptoms. We aim to describe the disease burden and oncologic outcomes of patients with HPV(+)OPSCC diagnosed >12 months after symptom onset.Study DesignThis is a retrospective cohort study of HPV(+)OPSCC patients receiving intent‐to‐cure treatment (including surgery ± adjuvant therapy or primary chemoradiation).Setting2006‐2016, tertiary care center.MethodsTumor stage was compared between patients with and without delayed diagnosis using χ2 tests. Kaplan‐Meier survival analysis with univariate and multivariable Cox regressions were used to determine the effect of diagnostic delay on oncologic outcomes.ResultsIn total, 664 patients were included. Compared to patients diagnosed <12 months from symptom onset (n = 601), those diagnosed at >12 months (n = 63) were more likely to have T4 disease and higher overall American Joint Committee on Cancer (AJCC) clinical stage at presentation (P <. 01 for both). At 5 years, rates of overall survival, cancer‐specific survival, progression‐free survival, and distant metastases–free survival in the delayed diagnosis cohort were 80%, 90%, 80%, and 89%, respectively. A >12‐month delay in diagnosis did not significantly impact overall survival (adjusted hazard ratio [aHR], 1.16; 95% CI, 0.58‐2.31), cancer‐specific survival (aHR, 0.83; 95% CI, 0.29‐2.39), progression‐free survival (aHR, 1.15; 95% CI, 0.56‐2.37), or distant metastases–free survival (aHR, 1.00; 95% CI, 0.42‐2.40) after adjusting for age, sex, and clinical AJCC stage (P >. 05 for all).ConclusionsDelayed diagnosis of HPV(+)OPSCC is associated with greater burden of disease at presentation, but oncologic outcomes remain favorable across treatment modalities. When appropriate, intent‐to‐cure therapy should be pursued despite diagnostic delay.Level of EvidenceLevel III.

AbstractBackgroundCutaneous squamous cell carcinomas (CSCC) involving the head and neck are common, but initial presentation or recurrence limited to the cranial nerves is rare.MethodsWe conducted a retrospective study of 21 patients with clinical perineural invasion (PNI) from CSCC and no measurable disease by RECIST 1.1. Patients treated with radiotherapy or chemoradiotherapy were included.ResultsThe median time from symptom onset until diagnosis was 13.0 months (2.6–83.1). All patients received radiotherapy. Fourteen received concurrent systemic therapy. The median follow‐up time was 30.5 months (1.1–106.0). Ten patients recurred, with the majority being locoregional. The 2‐year overall survival rate was 85%. The median progression‐free survival (PFS) was 21.5 months with an estimated 2‐year PFS of 44.5% (95%CI: 22.3–66.8).ConclusionsCSCCs with clinical PNI alone are difficult to diagnose and can have a long interval between appearance of symptoms and diagnosis. They can successfully be treated with chemoradiotherapy. However, many patients still suffer from locoregional recurrences.

Abstract Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

We sought to determine the incidence and location of human papillomavirus (HPV)–associated anogenital disease in women with HPV‐positive oropharyngeal squamous cell carcinoma (OPSCC) via a retrospective cohort study with prospective contact to update history at Mayo Clinic in Rochester, Minnesota. Females undergoing treatment for nonmetastatic HPV‐positive OPSCC from 2011 to 2019 were identified. Clinical history and outcomes were abstracted from medical records. Patients without documented anogenital history were contacted, consented, and administered a survey, and external records were requested and reviewed. Seventeen of 46 patients (37.0%) had a history of anogenital HPV‐associated disease, and 16 of 17 (94.1%) required procedures to diagnose or treat HPV lesions. The cervix was the most common site (16/17, 94.1%). Procedures included colposcopy (n = 6), cervical excision (n = 3), cryotherapy (n = 4), and hysterectomy (n = 3). One case of fatal cervical carcinoma was noted, diagnosed 1 year following OPSCC. Three of 17 (17.6%) had HPV‐related vulvovaginal disease, and 1 of 17 had anal disease. Patients with a history of HPV‐positive OPSCC may be at elevated risk for HPV‐associated anogenital disease.

6095 Background: Prognosis for patients (pts) with locally-advanced, HPV-positive oropharynx squamous cell carcinoma (HPV+OPSCC) is significantly better than for pts with HPV-negative head and neck squamous cell carcinoma (HNSCC). Historic survival of pts with metastatic HNSCC is 6-9 months with palliative therapy. However, the prognosis and survival of pts with HPV+OPSCC with distant metastases is not known. Methods: Pts with HPV+OPSCC with distant metastatic disease were identified from databases from the departments of surgery, radiation, and medical oncology. Demographic and clinical data was abstracted from the medical record. All pts had confirmed HPV/p16+ disease. Results: Fifteen pts with metastatic HPV+ OPSCC were identified. The median age was 57 years (range 42-78, 15 male). The median pack-year smoking was 0 (range 0-120). Primary site included 10 tonsil and 5 tongue base. At diagnosis, one pt had stage III and 14 had stage IV disease (IVA: 9, IVB: 2, IVC: 3). T- and N-stage included T1 (1), T2 (10), T3 (3), T4 (1) and N1 (1), N2a (1), N2b (9), N2c (3), N3 (1). Extracapsular extension was seen in 8 pts, absent in 2, and unknown in 5. Seven pts had lymph node (LN) involvement at level IV/V. Initial therapy for locally-advanced disease included surgery followed by adjuvant radiation (RT) in 1 pt and chemoRT in 8, and definitive chemoRT in 3 pts. Three pts were metastatic at initial diagnosis. Of 6 pts with an isolated metastatic site, 3 pts are alive > 2 years from diagnosis of metastasis (median 1.97 years, range 0.49-2.29). Palliative therapy included surgery (3), RT (9), platinum chemo +/- cetuximab (8), cetuximab alone (2) or with a taxane (2). The most common sites of metastasis included bone (6), lung (5), and LNs (5). The 1-year survival rate after diagnosis of metastatic disease was 92%. The median time to diagnosis of metastatic disease after definitive therapy was 0.47 years (95% CI 0.19-1.29); 75% of pts who developed metastatic disease did so within 1 year of definitive therapy. Of note, 2 of the 15 pts developed a secondary immune-mediated malignancy (melanoma and non-HIV associated Kaposi’s sarcoma). Conclusions: The survival of pts with metastatic HPV+OPSCC is significantly better than that of historic controls.