Chernock, Rebecca

Abstract Purpose: Relapse is a major cause of failure in human papillomavirus–independent head and neck squamous cell carcinoma. Clinicopathologic criteria for adjuvant treatment remain imprecise and have not changed for decades. We investigated whether ctDNA in lymphatic exudate collected via surgical drains (“lymph”) 24 hours after surgery identified molecular residual disease (MRD) and compared its performance with time-matched plasma. Experimental Design: Using an ultra-sensitive tumor-informed sequencing approach, tumor variants were called in lymph and plasma to classify patients as ctDNA positive or ctDNA negative, trained in an initial cohort of 36 patients, and replicated in an independent cohort of 37 patients. Progression-free survival was compared in ctDNA(+) versus ctDNA(–) patients. Results: Lymph identified MRD in two independent multi-site cohorts (initial cohort sensitivity = 76% and specificity = 63%; log-rank P = 0.01; replication cohort sensitivity = 65% and specificity = 70%; log-rank P = 0.04). Lymph performance was enhanced in locoregional relapse (sensitivity = 78% and specificity = 67%; log-rank P = 0.0004) and generalized to early-stage patients. Analysis of matched plasma collected at this early timepoint was not predictive of recurrence (sensitivity = 35% and specificity = 72%; log-rank P = 0.7). In patients with intermediate-risk pathology, lymph ctDNA was associated with recurrence (sensitivity = 88% and specificity = 67%; log-rank P = 0.0008), suggesting an opportunity for improved stratification of patients who may benefit from additional adjuvant treatment. Conclusions: Postoperative lymph is a novel, proximal, and early source of MRD with the potential to introduce more precision into adjuvant therapy decision-making and improve outcomes, especially for patients with intermediate-risk human papillomavirus–independent head and neck squamous cell carcinoma.

Inverted papilloma (IP) is a benign neoplasm of the nasal cavity and paranasal sinuses, known for its variable risk of recurrence and potential for developing carcinoma. Emerging evidence has shown high rates of activating EGFR mutation, and a smaller subset is associated with low-risk human papillomavirus (lrHPV). While certain morphologic features, including an inverted growth pattern, are well-established, the presence of condylomatous features, such as large fungating lesions with thick undulating surface epithelium, hyperkeratosis, cytoplasmic clearing, raisinoid nuclei, and binucleation (koilocytic changes) in low-risk HPV-associated IP suggests that these tumors may be a distinct subtype of sinonasal papilloma (SP) with features similar to low-risk HPV-associated anogenital condylomas. This study presents a series of SP with condylomatous morphology and explores the association with lrHPV, the clinicopathologic features, and the rates of carcinoma development. In total, 17 cases of SP exhibiting condylomatous morphology were retrospectively identified. We performed lrHPV and high-risk HPV (hrHPV) RNA in situ hybridization and p16 immunohistochemistry and gathered detailed clinical and pathologic data along with treatment, disease follow-up, and outcomes. These condylomatous papillomas almost all developed in active smokers, were large, were primarily located in the nasal cavity (47%), and showed frequent transformation to invasive squamous cell carcinoma (29%). This malignant transformation rate is much higher than what has been reported for inverted, exophytic, and oncocytic papillomas. The tumors were almost uniformly associated with transcriptionally-active lrHPV (94%) and were consistently negative for p16 and hrHPV. This study shows that a subgroup of IPs with condylomatous morphology have a predilection for the nasal cavity, strong association with lrHPV, and high rates of carcinoma. These findings support the concept that these tumors are a distinct (fourth) type of SP with a higher risk of malignant transformation.

Context.— In 2018, an evidence-based guideline was published by the College of American Pathologists to develop recommendations for the testing, application, interpretation, and reporting of high-risk human papillomavirus and surrogate marker tests in head and neck carcinomas. Substantial new evidence has prompted a review, including data on human papillomavirus (HPV) in nonoropharyngeal anatomic sites, HPV global rates, p16 immunohistochemistry, and HPV testing performance in cytology specimens, and performance of p16 immunohistochemistry as a surrogate marker. Objective.— To assess research published since the release of the original 2018 guideline and to update evidence-based recommendations for HPV testing in head and neck carcinomas. Design.— The College of American Pathologists convened a panel of experts to update the guideline following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The expert panel defined the key questions and performed a systematic review of the literature. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, recommendations were updated on the basis of available evidence, certainty of that evidence, and key judgments. Results.— Seven strong recommendations, 4 conditional recommendations, and 5 good practice statements are offered in the guideline update. Conclusions.— The updated guideline statements provide direction on the nature of HPV testing in various head and neck specimens (including key updates based on new research on sinonasal squamous cell carcinoma) and expanded guidance on specific scenarios and practice settings. The goal is to improve and standardize, where possible, HPV testing across diverse pathology practice settings and different countries.

DEK::AFF2 fusion nonkeratinizing squamous cell carcinoma (NKSCC) is an emerging entity in the sinonasal tract, temporal bone, and skull base. However, the clinical behavior of these tumors has not been well studied. Here, we report the largest cohort of DEK::AFF2 carcinomas to determine if morphology, mitotic rate, and/or Ki-67 IHC are associated with patient outcomes, including a comparison with high-risk human papillomavirus (HPV)-associated and independent patients. We solicited cases of molecularly or AFF2 immunohistochemistry (IHC) proven DEK::AFF2 SCC from surgical pathologists to collect patient demographic, clinical, and outcome data. Using representative H&E slides, we characterized the morphology and counted mitoses. Ki-67 immunohistochemistry was performed. We also compared the DEK::AFF2 survival rates to those in a cohort of AFF2 IHC-negative HPV-associated and HPV-independent SCC. DEK::AFF2 carcinomas most commonly arose in the nasal cavity (13/30, 43%), and the average number of recurrences was 1.8 (range: 0 to 10). At the last follow-up, most patients were disease free (19/30, 63%) or were alive with disease (9/30, 30%). There was an average mitotic rate of 2 per 2 mm2 (range: 0 to 9) and Ki-67 proliferation rate of 26% (range: 3% to 60%). Local recurrence was common, but morphology, mitotic activity, and Ki-67 index were not associated with recurrence or survival. On Kaplan-Meier survival analysis, DEK::AFF2 patients had lower disease-free survival but otherwise had similar outcomes to conventional SCC patients. Our multi-institutional study shows that local recurrence is common in DEK::AFF2 fusion nonkeratinizing SCC patients, but patients have survival rates similar to conventional SCC. Despite showing a range of different features and proliferation rates, traditional grading by morphology, mitotic rate, and/or Ki-67 activity does not seem to be predictive of outcome.

Abstract Context Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced as a new entity replacing the diagnosis of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC). Significant variability in the incidence of NIFTP diagnosed in different world regions has been reported. Objective To investigate the rate of adoption of NIFTP, change in practice patterns, and uniformity in applying diagnostic criteria among pathologists practicing in different regions. Methods Two surveys distributed to pathologists of the International Endocrine Pathology Discussion Group with multiple-choice questions on NIFTP adoption into pathology practice and whole slide images of 5 tumors to collect information on nuclear score and diagnosis. Forty-eight endocrine pathologists, including 24 from North America, 8 from Europe, and 16 from Asia/Oceania completed the first survey and 38 the second survey. Results A 94% adoption rate of NIFTP by the pathologists was found. Yet, the frequency of rendering NIFTP diagnosis was significantly higher in North America than in other regions (P = .009). While the highest concordance was found in diagnosing lesions with mildly or well-developed PTC-like nuclei, there was significant variability in nuclear scoring and diagnosing NIFTP for tumors with moderate nuclear changes (nuclear score 2) (case 2, P < .05). Pathologists practicing in North America and Europe showed a tendency for lower thresholds for PTC-like nuclei and NIFTP than those practicing in Asia/Oceania. Conclusion Despite a high adoption rate of NIFTP across geographic regions, NIFTP is diagnosed more often by pathologists in North America. Significant differences remain in diagnosing intermediate PTC-like nuclei and respectively NIFTP, with more conservative nuclear scoring in Asia/Oceania, which may explain the geographic differences in NIFTP incidence.

PURPOSE The volume treated with postoperative radiation therapy (PORT) is a mediator of toxicity, and reduced volumes result in improved quality of life (QOL). In this phase II trial, treatment volumes were reduced by omitting PORT to the pathologically negative (PN0) neck in patients with primary head and neck squamous cell carcinoma. METHODS Patients with head and neck squamous cell carcinoma who underwent surgical resection and neck dissection with a PN0 neck and high-risk features mandating PORT to the primary and/or involved neck were eligible. The primary end point was greater than 90% disease control in the unirradiated neck. QOL was evaluated using the MD Anderson Dysphagia Inventory and the University of Michigan patient-reported xerostomia questionnaire. RESULTS Seventy-three patients were enrolled, and 72 were evaluable. Median age was 56 years (range, 31 to 81 years); 58 patients were male, and 47 (65%) had a smoking history. Sites included oral cavity (n = 14), oropharynx (n = 37), hypopharynx (n = 4), larynx (n = 16), and unknown primary tumor (n = 1). According to the American Joint Committee on Cancer Staging Manual (7 th edition), 67 patients (93%) had stage III/IV disease, and 71% of tumors involved or crossed midline. No patient had contralateral neck PORT. In 17 patients (24%), only the primary site was treated. At a median follow-up of 53 months, two patients experienced treatment failure of the PN0 unirradiated neck; they also experienced treatment failure locally. Unirradiated neck control was 97% (95% CI, 93.4% to 100.0%). Five-year rates of local control, regional control, progression-free survival, and overall survival were 84%, 93%, 60%, and 64%, respectively. QOL measures were not significantly different from baseline at 12 and 24 months post-PORT ( P > .05). CONCLUSION Eliminating PORT to the PN0 neck resulted in excellent control rates in the unirradiated neck without long-term adverse effects on global QOL.