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Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer- associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC., Introduction Anaplastic thyroid cancer (ATC), characterized by an undifferentiated morphology, is arguably one of the most lethal malignancies. According to Surveillance, Epidemiology and End Results (SEER) data (released April 2021) [...]

The incidence of human papilloma virus–mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory–afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship. Editor's summary: Patients with human papilloma virus (HPV)–mediated oropharyngeal squamous cell carcinoma (OPSCC) often have a good prognosis; however, standard of care treatment often leads to poor side effects such as dysphagia. To better understand this link, Islam et al. evaluated patient sample neural landscapes and correlated these with patient outcomes. They saw that tumor enrichment of adrenergic and CGRP+ nerves correlated with worse swallowing outcomes. They further evaluated this mechanism in a mouse model and suggest that CGRP blockers may help preserve swallow function in patients; however, this will require further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

This article presents a case study of a 51-year-old Caucasian male with advanced oral cavity cancer who underwent neoadjuvant chemotherapy followed by surgery and radiation therapy. The treatment was successful, resulting in tumor regression and improved pain and eating. The article also discusses the importance of surgical factors and the conflicting results regarding the impact of neoadjuvant therapy on outcomes. Perspectives from plastic surgery, pathology, radiation oncology, speech pathology, and a patient's experience are provided. The document concludes by discussing future directions, including the potential use of immunotherapy. [Extracted from the article]

Histopathology plays a critical role in the diagnosis and surgical management of cancer. However, access to histopathology services, especially frozen section pathology during surgery, is limited in resource-constrained settings because preparing slides from resected tissue is time-consuming, labor- intensive, and requires expensive infrastructure. Here, we report a deep- learning-enabled microscope, named DeepDOF-SE, to rapidly scan intact tis- sue at cellular resolution without the need for physical sectioning. Three key features jointly make DeepDOF-SE practical. First, tissue specimens are stained directly with inexpensive vital fluorescent dyes and optically sectioned with ultra-violet excitation that localizes fluorescent emission to a thin surface layer. Second, a deep-learning algorithm extends the depth-of-field, allowing rapid acquisition of in-focus images from large areas of tissue even when the tissue surface is highly irregular. Finally, a semi-supervised generative adversarial network virtually stains DeepDOF-SE fluorescence images with hematoxylin-and-eosin appearance, facilitating image interpretation by pathologists without significant additional training. We developed the DeepDOF-SE platform using a data-driven approach and validated its performance by imaging surgical resections of suspected oral tumors. Our results show that DeepDOF-SE provides histological information of diagnostic importance, offering a rapid and affordable slide-free histology platform for intraoperative tumor margin assessment and in low-resource settings. [ABSTRACT FROM AUTHOR]

* Standardized pathologic reporting for cancers allows for improved communication for patient care and prognostic determination. If used universally, synoptic reporting enhances comparing data globally for scientific leverage. The International Collaboration on Cancer Reporting is a nonprofit organization whose mission is to develop evidence-based, universally available surgical pathology reporting data sets. Multiple different sites within the head and neck may be affected by mucosal melanoma, whose behavior and patient outcome are not equivalent to carcinomas of the corresponding sites. Factors such as Breslow thickness and Clark depth of invasion applied to cutaneous melanomas do not yield any prognostic significance in mucosal sites, and thus are not meaningful. Likewise, margin assessment is unique in head and neck sites. Further, the genetic profile of mucosal melanomas is different from that of most cutaneous tumors. Thus, within the head and neck region, mucosal melanoma is a distinct entity for which a dedicated data set was developed for implementation. The elements that comprise the core (required) and noncore (recommended) elements are discussed. doi: 10.5858/arpa.2018-0412-SA, Standardized pathologic reporting for cancers is a process that allows for improved communication for patient care and prognostic determination. When the same standardization is expanded beyond a single institution or [...]

Standardized, synoptic pathologic reporting for tumors greatly improves communication among clinicians, patients, and researchers, supporting prognostication and comparison about patient outcomes across institutions and countries. The International Collaboration on Cancer Reporting is a nonprofit organization whose mission is to develop evidence-based, universally available surgical pathology reporting data sets. Within the head and neck region, lymph node excisions and neck dissections are frequently performed as part of the management of head and neck cancers arising from the mucosal sites (sinonasal tract, nasopharynx, oropharynx, hypopharynx, oral cavity, and larynx) along with bone tumors, skin cancers, melanomas, and other tumor categories. The type of specimen, exact location (lymph node level), laterality, and orientation (by suture or diagram) are essential to accurate classification. There are significant staging differences for each anatomic site within the head and neck when lymph node sampling is considered, most importantly related to human papillomavirus-associated oropharyngeal carcinomas and mucosal melanomas. Number, size, and site of affected lymph nodes, including guidelines on determining the size of tumor deposits and the presence of extranodal extension and soft tissue metastasis, are presented in the context of prognostication. This review elaborates on each of the elements included in the data set for Nodal Excisions and Neck Dissection Specimens for Head & Neck Tumours. (Arch Pathol Lab Med. 2019;143:452-462; doi: 10.5858/arpa.2018-0421-SA), The International Collaboration on Cancer Reporting (ICCR) was established in 2011 through a collaboration among the College of American Pathologists, the Canadian Association of Pathologists-Association Canadienne des Pathologists in association [...]

* Context.--Human papillomavirus (HPV) DNA in situ hybridization (ISH) assay and p16 immunohistochemistry (IHC) are used to determine high-risk HPV status in formalin-fixed, paraffin-embedded (FFPE) tissues in oropharyngeal squamous cell carcinoma (SCC). Although high sensitivity and specificity for HPV can be obtained by combined p16 IHC and HPV DNA ISH, the occasional discrepancy between these assays has prompted evaluation of Cervista HPV assays in FFPE tissue from patients with oropharyngeal SCC. Objective.--To compare the efficacy of Cervista HPV 16/18 and Cervista HPV HR assay to that of HPV DNA ISH assay and p16 IHC in FFPE tissue in head and neck squamous cell carcinoma of oropharyngeal origin. Design.--Archived FFPE tissue from 84 patients with SCC of oropharyngeal origin and available HPV DNA ISH and p16 IHC test results were tested with the Cervista HPV 16/18 assay and further verified by polymerase chain reaction (PCR)-based HPV16/18 genotyping tests in cases with discrepancy. Results.--Of the 84 specimens, 75% (63 of 84) were positive and 16% (13 of 84) had discrepant or equivocal findings by p16 IHC and HPV DNA ISH testing. Use of Cervista HPV assays, either to clarify discrepant/equivocal findings or as confirmation after initial p16 IHC/HPV DNA ISH tests, identified 81% (68 of 84) of HPV-positive cases without equivocal HPV results. Five of 13 cases with discrepancy or equivocal HPV DNA ISH results tested positive for HPV16 or HPV18 by Cervista HPV 16/18 assay, which was further confirmed by PCR-based HPV 16/18 genotyping. Conclusions.--The Cervista HPV assays are a reasonable alternative to HPV DNA ISH in determining HPV status in FFPE tissue specimens from patients with oropharyngeal SCC. doi: 10.5858/arpa.2017-0469-OA, Prior infection with high-risk human papillomavirus (hrHPV), predominantly the HPV16 type, has been recognized as an etiologic factor in most oropharyngeal squamous cell carcinomas (SCCs) and a small proportion of [...]

Background: Use of postoperative radiation therapy (PORT) in locoregionally advanced medullary thyroid cancer (MTC) remains controversial. The objective was to evaluate the effect of PORT on locoregional control (LRC) and overall survival (OS). Methods: Retrospective cohort study of 346 MTC patients separated into PORT and no‐PORT cohorts. Relative indications for PORT, as well as changes in patterns of treatment, were recorded. Results: 49/346 (14%) received PORT. PORT was associated with worse OS; adjusted HR = 2.0 (95%CI 1.3–3.3). PORT was not associated with improved LRC, even when adjusting for advanced stage (Stage III p = 0.892; Stage IV p = 0.101). PORT and targeted therapy were not associated with improved OS compared to targeted therapy alone; adjusted HR = 1.2 (95%CI 0.3–4.1). Conclusions: Use of PORT in MTC has decreased and its indications have become more selective, coinciding with the advent of effective targeted therapies. Overall, PORT was not associated with improved LRC or OS. [ABSTRACT FROM AUTHOR]

Background: Sinonasal NUT carcinoma is an extremely rare, lethal malignancy with limited literature. Methods: A case series was conduction of all patients with sinonasal NUT carcinoma at a single institution between 2010 and 2022. Survival and associated were evaluated. A systematic review of the literature was performed. Results: In 12 patients, followed for a median of 1.5 years, the median overall survival (OS) and disease‐specific survival (DSS) were both 14.6 months. Patients with maxillary sinus tumors were 91% more likely to survive (hazard ratio [HR]: 0.094, 95% confidence interval [CI]: 0.011–0.78, p = 0.011). Patients with higher‐stage disease stage had worse OS (stage IVb‐c vs. III‐IVa, p = 0.05). All three patients who were alive with no evidence of disease received induction chemotherapy. Conclusion: For patients with sinonasal NUT carcinoma, the median survival was 15 months but better with lower‐stage and maxillary tumors. Induction chemotherapy may be beneficial. [ABSTRACT FROM AUTHOR]